Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline

Chemistry. 2022 Aug 22;28(47):e202201311. doi: 10.1002/chem.202201311. Epub 2022 Jul 7.

Abstract

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Keywords: bedaquiline; continuous flow; diastereoselectivity; lithiation; nucleophilic addition.

MeSH terms

  • Antitubercular Agents
  • Diarylquinolines / therapeutic use
  • Humans
  • Mycobacterium tuberculosis*
  • Reproducibility of Results
  • Tuberculosis* / drug therapy

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • bedaquiline