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. Epub 2016 Feb 18.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Benzyl Compounds / chemical synthesis*
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology
  • Biological Phenomena
  • Cyclization
  • Isotope Labeling
  • Nitro Compounds / chemical synthesis*
  • Nitro Compounds / chemistry
  • Nitro Compounds / pharmacology
  • Nitroso Compounds / chemical synthesis*
  • Nitroso Compounds / chemistry
  • Nitroso Compounds / pharmacology
  • Receptors, Thyroid Hormone / agonists*
  • Receptors, Thyroid Hormone / chemistry*
  • Receptors, Thyroid Hormone / metabolism
  • Structure-Activity Relationship

Substances

  • 2-(4-((7-Isopropyl-2-(4-nitrophenyl)benzofuran-5-yl)methyl)-3,5-dimethylphenoxy)acetic acid
  • 2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid
  • Benzofurans
  • Benzyl Compounds
  • Nitro Compounds
  • Nitroso Compounds
  • Receptors, Thyroid Hormone