Enzyme engineering, enzyme immobilization and flow chemistry to enable the production of key intermediate en-route to nemtabrutinib

Dr. Karla Camacho Soto 
Assistant Principal Scientist
Merck & Co

Seminar Abstract: Biocatalysis, protein engineering, and flow chemistry are key enabling technologies that can yield drastically shorter and greener chemical processes. We sought to leverage these technologies to improve the synthesis of a chiral intermediate en-route to nemtabrutunib. CyreneTM, a green chemical commodity, along with a transaminase allowed the generation of the cyrene-amine chiral intermediate in a stepwise reaction in modest yields and selectivity. We sought to engage in enzyme engineering to improve yield, selectivity and thermostability of the catalyst to support synthesis at scale. During process development difficulties in isolating the highly soluble cyrene-amine intermediate from aqueous streams and the formation of an aldol by-product under aqueous conditions opened the door to employ enzyme immobilization and flow chemistry to improve process conditions in the presence of organic solvents. The combination of enzyme engineering, enzyme immobilization and flow chemistry in the presence of 2-MeTHF allowed the production of the cyrene-amine intermediate in high yield and selectivity.