(610c) Biaryl Phosphorinane Ligands Flow Chemistry Scale-up

A series of Biaryl Phosphorinane ligands was synthesized by AbbVie to aid catalysis in a variety of small molecule active pharmaceutical ingredient (API) intermediate synthesis. The first step of the process to produce the ligands was manufactured in the AbbVie API Pilot Plant via flow chemistry. The flow chemistry process used a combination of plug flow reactors (PFRs) and continuously stirred reactors (CSTRs) to facilitate three consecutive reaction steps. Process analytical technology (PAT), including Fourier Transform Infrared Spectroscopy (FTIR) and continuous High Performance Liquid Chromatography (HPLC), was used to monitor reaction progress. The reaction was manufactured in flow as a safety consideration due to the large volume of n-butyllithium required to produce the desired quantity of product. Novel techniques were used to optimize and derisk the process at the lab scale before scaling up to the pilot plant. Several challenges were encountered at scale, including unexpected precipitation, large reaction autothermal reforming (ATR), and unique equipment requirements, which were addressed with process modifications throughout the process design and manufacturing campaign.