Tetrahedron p. 2385 - 2399 (2019)
Update date:2022-08-06
Topics:
Heckrodt, Thilo J.
Chen, Yan
Singh, Rajinder
An extensive medicinal chemistry campaign and subsequent SAR studies led to the discovery of the highly potent and selective JAK1/3 inhibitor R545. To support advanced pre-clinical DMPK studies of R545, the isotopically labeled versions of the drug and its metabolite R935 were required. Herein, we describe the development of synthetic routes to deuterium-labeled [D7]-R545 and its oxidative metabolite [D7]-R935. Deuterium atoms were introduced at several sites in the target molecules by employing a convergent synthesis strategy. The desired regiochemistry at the right-hand side of [D7]-R935 was established via a newly discovered protecting group-directed bromination. The described synthetic approach gave rise to the desired deuterium-labeled target compounds and sufficient quantities were synthesized to enable pre-clinical DMPK studies.
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