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.
Alternative routes to the arylethanolamine subunit of a development drug have been investigated. The selected route,
involving O-alkylation of a phenol using N-benzyloxathiazolidine-S-oxide, was developed to give a process used successfully
for pilot plant manufacture.
Application of Oxathiazolidine-S-oxide Chemistry to the Large-Scale Single-Step Synthesis of an O-Arylethanolamine. -The synthesis of target amine (III) by O-alkylation of phenol (I) with the oxathiazolidine-S-oxide (II) instead with N-benzylethanolamine is successfully used for pilot plant manufacture. -(BARKER, ALAN C.; BOARDMAN, KAY A.; BROADY, SIMON D.; MOSS, WILLIAM O.; PATEL, BHARTI; SENIOR, MICHAEL W.; WARREN, KENNETH E. H.; Org. Process Res. Dev. 3 (1999) 4, 253-255; Proc. Dev. Dep., Zeneca Pharm., Macclesfield, Cheshire SK10 2NA, UK; EN)
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