Scale-Up Preparation of Best-In-Class Orally Bioavailable CXCR4 Antagonist EMU-116 in an Academic Setting

CXCR4 is a seven-transmembrane chemokine receptor that is intimately involved in stem cell niche maintenance and immune cell trafficking. Among several other pathophysiological states for which CXCR4 mis regulation is implicated, various hematological malignancies and solid tumors hijack this chemokine network by dramatically overexpressing CXCR4 and its cognate chemokine ligand CXCL12. Upregulation of the CXCR4/CXCL12 axis in cancer drives tumor progression through several mechanisms, which makes CXCR4 a promising target for the development of anticancer therapeutics. Herein, we report the preparative scale synthesis of a novel, best-in-class, orally bioavailable small molecule CXCR4 antagonist, EMU-116. Two synthetic strategies for production of EMU-116 were pursued. While the first discovery-focused synthesis facilitated late-stage diversification to drive structure–activity relationship determinations, the second process-focused synthesis delivered EMU-116 more efficiently in higher overall yield with enhanced stereocontrol. For both synthetic routes, Buchwald–Hartwig amination of key aryl bromide intermediates enabled installation of the N-methylpiperazine appendage of EMU-116. Synthetic methods devised to prepare (R)-9-bromo-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one, the key aryl bromide intermediate required for the process-focused synthesis, are reported. In addition, an improved preparative method of known synthon (S)–N-methyl-5,6,7,8-tetrahydroquinolin-8-amine is highlighted by elevated overall yield, enhanced diastereoselectivity, and robust purification by crystallization. Further elaboration of these two intermediates, coupling via reductive amination to furnish the full EMU-116 scaffold, removal of protecting groups, and final product purification techniques are also reported. Overall, the synthetic methods described herein enabled reliable and efficient production of multigram quantities of EMU-116 and are anticipated to be amenable to larger scale production.