Chasing the Elusive Benzofuran Impurity of the THR Antagonist NH-3: Synthesis, Isotope Labeling, and Biological Activity

We
have synthesized and established the structure of a long-suspected,
but hitherto unknown, benzofuran side product (EBI) formed during
the synthesis of NH-3. Understanding the mechanism of its formation
has enabled isotope (D) labeling. We further developed a highly efficient
method for separating EBI from NH-3. Interestingly, EBI was found
to be a very potent thyroid hormone receptor (THR) agonist, while
NH-3 is an antagonist. In this process, we have also achieved a significantly
improved synthesis of NH-3.