Development of Commercial Manufacturing Processes for Acalabrutinib

Abstract

The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved in a short timeframe. Issues are discussed, such as the uncontrolled epimerization of a chiral center and the control of the acalabrutinib 1 crystallization step, which was prone to oiling. Specifically, work to understand the complex polymorph landscape of a key intermediate (to facilitate resolution of a filtration issue) is described.

(o-CF3PhO)3P as a simple coupling reagent for direct amidation via activation of amines

“…On this basis, the drug intermediate AMG-47a (Lck inhibitor) 13 was synthesized by direct amidation in excellent yields of 99% ( P6 ). Aliphatic amines were also successfully introduced into the reaction system and the target compounds ( P7–P9 ) were prepared in good to excellent yields, and among them moclobemide 14 ( P9 ) was obtained in up to 95% yield via direct amidation. Generally, the direct amination of sterically hindered substrates is almost impossible to achieve.…”