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 “plug flow” reactor scheme allowing sufficient residence time for reaction completion. The process has been scaled-up to the pilot plant and to manufacturing.

• Bristol-Myers Squibb

• Intermediate

1. Brivanib Alaninate
2. Continuous Plug Flow Process
3. Heat exchange
4. Intermediate
5. Oxides
6. Research Article
7. Scale-up
8. thermal runaway