35 research outputs found
Multi-Kilo Delivery of AMG 925 Featuring a Buchwald–Hartwig Amination and Processing with Insoluble Synthetic Intermediates
The
development of a synthetic route to manufacture the drug candidate
AMG 925 on kilogram scale is reported herein. The hydrochloride salt
of AMG 925 was prepared in 23% overall yield over eight steps from
commercially available raw materials, and more than 8 kg of the target
molecule were delivered. The synthetic route features a Buchwald–Hartwig
amination using BrettPhos as ligand and conducted to afford 12 kg
of product in a single batch. In addition, this work highlights the
challenges associated with the use of poorly soluble process intermediates
in the manufacture of active pharmaceutical ingredients. Creative
solutions had to be devised to conduct seemingly routine activities
such as salt removal, pH adjustment, and heavy metal scavenging due
to the low solubility of the process intermediates. Finally, a slurry-to-slurry
amidation protocol was optimized to allow for successful scale-up