Development of a Continuous Plug Flow Process for Preparation of a Key Intermediate for Brivanib Alaninate

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• 作者：Thomas L. LaPorte ; Lori Spangler ; Mourad Hamedi ; Paul Lobben ; Steven H. Chan ; Jale Muslehiddinoglu ; Steve S. Y. Wang
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：November 21, 2014
• 年：2014
• 卷：18
• 期：11
• 页码：1492-1502
• 全文大小：738K
• ISSN：1520-586X

文摘

A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the hazard analysis, process development, reactor development, reaction engineering model development, and scale-up of the continuous process. The process includes three separate and stable feed streams that are mixed in distinct order using in-line static mixers. Heat exchangers are arranged and connected to facilitate a 鈥減lug flow鈥?reactor scheme allowing sufficient residence time for reaction completion. The process has been scaled-up to the pilot plant and to manufacturing.