From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme‑, Iridium‑, and Palladium-Catalyzed Key Transformations

With the first generation medicinal chemistry synthesis as a starting point, we describe herein process development of AZD4573, an oncology drug candidate. In addition to improved yields and removal of chromatographic steps, we have addressed other factors such as availability of starting materials as well as safety of the chemistry involved. With several steps involving volatile, reactive, and non-UV active materials, reaction optimization was facilitated by implementing off-line 1H NMR analysis of crude mixtures. Key transformations targeted for process development included a Wolff–Kishner reduction, an iridium-catalyzed borylation, and enzymatic resolution of a racemic amino-ester.