The Development of a Dimroth Rearrangement Route to AZD8931

Recently, the aminoquinazoline motif has been highly prevalent in anticancer pharmaceutical compounds. Synthetic methods are required to make this structure on a multikilo scale and in high purity. The initial route to aminoquinazoline AZD8931 suffered from the formation of late-stage impurities. To avoid these impurities, a new high-yielding Dimroth rearrangement approach to the aminoquinazoline core of AZD8931 was developed. Assessment of route options on a gram scale demonstrated that the Dimroth rearrangement is a viable approach. The processes were then evolved for large-scale production with learning from a kilo campaign and two plant-scale manufactures. Identification of key process impurities offers an insight into the mechanisms of the Dimroth rearrangement as well as the hydrogenation of a key intermediate. The final processes were operated on a 30 kg scale delivering the target AZD8931 in 41% overall yield.