Development of a Convergent and Scalable Synthetic Route to Long-Acting RSV Inhibitor JNJ-7950

JNJ-7950 is a potent small-molecule respiratory syncytial virus (RSV) inhibitor with a long-acting profile in preclinical species. The design and development of a convergent synthetic route accelerated the discovery and development of JNJ-7950. First, the new synthetic route supported the lead candidate (JNJ-7950) selection process and later was adapted to provide a large-scale clinical batch. A shorter and cost-effective synthetic route to the key spiro-azetidine moiety exploited an intramolecular copper-catalyzed C–N coupling. The development of an efficient and sustainable process for telescoping three steps in a single solvent provided the benzimidazole moiety with an 85% overall yield. The spiro-azetidine and the benzimidazole moieties were coupled to provide JNJ-7950 in 48% overall yield with excellent purity over the six longest linear steps. Two GMP batches (6 and 12 kg) of JNJ-7950 were manufactured in parenteral grade quality to support long-acting injectable formulation development and early clinical need.