Abstract

Process Development of a Diastereopure Drug Intermediate via Flash Chemistry, Continuous Packed-bed Hydrogenation and Enzymatic Kinetic Resolution

Fanfu Guan, Senior Scientist, Jiangsu Hengrui Pharmaceuticals Co. Ltd.

New technologies, such as continuous flow chemistry and enzymatic catalysis, are reshaping drug development and production, assisting in synthesis of drug with precision. HRS-1358 is a novel PROTAC molecule designed to target and degrade the estrogen receptor (ER). It potently and selectively degrades ER, inhibits ER transcriptional activity and downstream signaling, thereby suppressing tumor cell proliferation and exerting anti-tumor effects. The synthesis of key drug intermediate 1 possessing two sterically hindered adjacent stereocenters lacking chelating heteroatoms, presents significant challenges. To meet the clinical trial demands, the new synthetic route in Figure 1 was developed by adopting continuous flash chemistry, continuous packed bed hydrogenation and enzymatic kinetic resolution, raising the yield by two-fold to 32.5% and reducing the step to three steps.