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

Abstract

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.

Model-Based Scale-Up Predictions: From Micro- to Millireactors Using Inline Fourier Transform Infrared Spectroscopy

“…As flow chemistry offers many benefits over batch chemistry, the use of microstructured devices within organic syntheses is of high interest. − Especially in the case of strong exothermic organometallic reactions, continuous flow microreactors permit safe handling due to short residence times and very efficient heat and mass transfer. − However, unintended decomposition reactions of intermediates can be minimized, and processes can be carried out in a controllable manner even at higher temperatures. , In addition, better yields and improved selectivity can be accomplished. − By using microreactors within experiments on a laboratory scale, well-defined reaction conditions are established. These allow for assuming nearly optimal conditions close to ideal plug flow reactor behavior.…”

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

“…Continuous processing is a powerful alternative to classic batch chemistry and is often applied to procedures where safety (high temperatures, pressures, large exotherms and aggressive reagents) and fast heat or mass transfer (bi- and triphasic systems, reactions with gases or light) have a major impact . Pharmaceutical companies have embraced continuous technologies to benefit from fully automatic processes and a continuous analytical data stream while using dedicated, inexpensive equipment where scale–up often involves a longer running time . These methodologies are also easily aligned with the majority of the highest standards of quality and green chemistry principles recommended by the FDA and EPA .…”

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

“…As seen above, avoiding detrimental exotherms in scale up campaigns is a common reason for developing a continuous flow process. This approach is also demonstrated in the synthesis of the pyrrolotriazinone 73 via a exothermic oxidative rearrangement from 75 , a key intermediate towards brivanib alaninate ( 74 ) that was reported by researchers at BMS in 2014 ( Scheme 12 ) [ 72 ].…”