Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib

The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.