From Chiral Separation to Asymmetric Synthesis: Route Scouting and Early Process Development of a Chiral Tetrahydrofuran–Pyrazolamine Intermediate of CDK2 Inhibitor <b>RLY-2139</b>

The development of RLY-2139, a selective orthosteric CDK2 inhibitor for ER+/HER2– breast cancer, necessitates a scalable and enantioselective synthesis of a key chiral intermediate, the chiral tetrahydrofuran pyrazolamine (compound 2). The initial synthetic route, culminating in a low-yielding final-step chiral separation of rac-2a, provided 2a in only a 2% overall yield. Recognizing the need for improved efficiency and sustainability, we explored several alternative strategies, including biocatalysis and various asymmetric routes. However, these were limited by challenges such as epimerization, poor diastereoselectivity, or limited scalability. Ultimately, a robust and scalable process was established using hydrolytic kinetic resolution (HKR) of terminal epoxide 27, delivering enantiomerically pure 2b. This intermediate was successfully converted to 3 in a kilo-lab campaign with an overall yield of 11%. The optimized 8-step route toward 2b was highly telescoped, chromatography-free, incorporating multiple impurity purges, making the process highly efficient. This process was successfully demonstrated on a multikilogram scale, providing a practical and industrially viable method for large-scale production of a critical pharmaceutical intermediate.