Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals

Yuta Takamura, Ken Ichi Morishita, Shota Kikuzawa, Masaki Watanabe, Hiroki Kakuta

Research output: Contribution to journalArticlepeer-review

Abstract

Small-molecular drugs, which are generally inexpensive compared with biopharmaceuticals and can often be taken orally, may contribute to the Sustainable Development Goals (SDGs) adopted by the United Nations. We previously reported the retinoid X receptor (RXR) agonist 4-(ethyl(3-isobutoxy-4-isopropyl-phenyl)amino)benzoic acid (NEt-3IB, 1) as a small-molecular drug candidate to replace biopharmaceuticals for the treatment of inflammatory bowel disease. The previous synthetic method to 1 required a large amount of organic solvent and extensive purification. In line with the SDGs, we aimed to develop an environmentally friendly, inexpensive method for the large-scale synthesis of 1. The developed method requires only a hydrophobic ether and EtOH as reaction and extraction solvents. The product was purified by recrystallization twice to afford 99% pure 1 at 100mmol scale in about 30% yield. The optimized process showed a 35-fold improvement of the E-factor (an index of environmental impact) compared to the original method. This work, which changes the solvent used to environmentally preferable ones based on the existing synthetic method for 1, illustrates how synthetic methods for small-molecular drugs can be adapted and improved to contribute to the SDGs.

Original languageEnglish
Pages (from-to)146-154
Number of pages9
JournalChemical and Pharmaceutical Bulletin
Volume70
Issue number2
DOIs
Publication statusPublished - Feb 1 2022

Keywords

  • Green sustainable chemistry
  • Inflammatory bowel disease
  • Process chemistry
  • Retinoid X receptor
  • Sustainable Development Goal

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery

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