Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 22;28(47):e202201311.
doi: 10.1002/chem.202201311. Epub 2022 Jul 7.

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

Sarah Jane Mear  1 , Tobias Lucas  2 , Grace P Ahlqvist  1 , Juliana M S Robey  3 , Jule-Philipp Dietz  2 , Pankaj V Khairnar  3 , Sanjay Maity  3 , Corshai L Williams  1 , David R Snead  3 , Ryan C Nelson  3 , Till Opatz  2 , Timothy F Jamison  1
Affiliations

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

Sarah Jane Mear et al. Chemistry. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Industrial synthesis of bedaquiline fumarate.
Figure 1
Figure 1
Mechanistic investigation of the lithiation/1,2‐addition sequence for synthesis of 1.
Figure 2
Figure 2
Evaluation of lithium amide bases in the lithiation/1,2‐addition sequence.
Figure 3
Figure 3
(a) Investigation of the influence of salt additives on d.r. of the 1,2‐addition reaction using commercial LDA solution as base. Diastereomer percentage composition determined by HPLC. (b) Assay of LiBr additive on d.r. and yield of 1,2‐addition with different lithium amide bases. Yield determined by 1H NMR spectroscopy using 1,4‐bis(trimethylsilyl)benzene as internal standard.
See this image and copyright information in PMC

References

    1. Wiens K. E., Woyczynski L. P., Ledesma J. R., Ross J. M., Zenteno-Cuevas R., Goodridge A., Ullah I., Mathema B., Djoba Siawaya J. F., Biehl M. H., Ray S. E., Bhattacharjee N. V., Henry N. J., Reiner R. C. Jr., Kyu H. H., Murray C. J. L., Hay S. I., BMC Med. 2018, 16, 196. - PMC - PubMed
    1. Global tuberculosis report 2021. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/teams/global-tuberculosis-programme/tb-reports.
    1. Médecins Sans Frontières Issue Brief: DR-TB Drugs Under the Microscope, 6th edition. October, 2019.
    1. Calvert M. B., Furkert D. P., Cooper C. B., Brimble M. A., Bioorg. Med. Chem. Lett. 2020, 30, 127172. - PubMed
    1. Cox E., Laessig K., N. Engl. J. Med. 2014, 371, 689–691. - PubMed