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

  • J Org Chem. 2016 Mar 4;81(5):1870-6. doi: 10.1021/acs.joc.5b02665.
Latika Singh  1 ,  Brandon Pressly  1 ,  Brenda J Mengeling  2 ,  James C Fettinger  3 ,  J David Furlow  2 ,  Pamela J Lein  4 ,  Heike Wulff  1 ,  Vikrant Singh  1
Affiliations
  • 1. Department of Pharmacology, University of California , Davis, California 95616, United States.
  • 2. Department of Neurobiology, Physiology, and Behavior, University of California Davis, California 95616, United States.
  • 3. Department of Chemistry, University of California , Davis, California 95616, United States.
  • 4. Department of Molecular Biosciences, School of Veterinary Medicine, University of California , Davis, California 95616, United States.
PMID: 26849160 DOI: 10.1021/acs.joc.5b02665
Abstract

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.

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