Manufacture of a key intermediate in the synthesis of AMG 193 using continuous manufacturing

Abstract: AMG 193 is a cooperative inhibitor of PRMT5 with methylthioadenosine (MTA), selectively inhibiting PRMT5 in methythioadenosine phosphorylase (MTAP) null cancers, and is currently progressing through clinical trials. This presentation will discuss various aspects of the end-to-end commercial process development for a key chiral morpholine fragment (CFAM) in the synthesis of AMG 193, with a focus on the continuous manufacturing (CM) of a ketone intermediate, TOMBOC. TOMBOC is generated from an aryl bromide and morpholinone via a highly reactive aryl lithium intermediate. This talk will highlight the development of this multistep CM process to enable large-scale manufacture of TOMBOC. To maximize time and material efficiency, transient flow experiments – which involve the continuous manipulation of reaction parameters in a controlled manner within a single run – were used in the process optimization. Overall, this robust flow process delivers excellent purity TOMBOC while offering safety and cost improvements over previous magnesium-based syntheses. Next, TOMBOC undergoes a deprotection and cyclization to form an imine CFIM. Finally, CFIM undergoes biocatalytic asymmetric reduction using an imine reductase (IRED) catalyst to produce CFAM, which is isolated as a hydrochloride salt. Ultimately, >900 kg of CFAM.HCl has been produced in high quality (100 A% purity, meeting all proposed commercial specifications) to support fast-moving clinical supply demands.