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.