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

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 bedaqu...

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Autores principales: Mear, Sarah Jane, Lucas, Tobias, Ahlqvist, Grace P., Robey, Juliana M. S., Dietz, Jule‐Philipp, Khairnar, Pankaj V., Maity, Sanjay, Williams, Corshai L., Snead, David R., Nelson, Ryan C., Opatz, Till, Jamison, Timothy F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9545417/
https://www.ncbi.nlm.nih.gov/pubmed/35675114
http://dx.doi.org/10.1002/chem.202201311
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author Mear, Sarah Jane
Lucas, Tobias
Ahlqvist, Grace P.
Robey, Juliana M. S.
Dietz, Jule‐Philipp
Khairnar, Pankaj V.
Maity, Sanjay
Williams, Corshai L.
Snead, David R.
Nelson, Ryan C.
Opatz, Till
Jamison, Timothy F.
author_facet Mear, Sarah Jane
Lucas, Tobias
Ahlqvist, Grace P.
Robey, Juliana M. S.
Dietz, Jule‐Philipp
Khairnar, Pankaj V.
Maity, Sanjay
Williams, Corshai L.
Snead, David R.
Nelson, Ryan C.
Opatz, Till
Jamison, Timothy F.
author_sort Mear, Sarah Jane
collection PubMed
description 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.
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spelling pubmed-95454172022-10-14 Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline Mear, Sarah Jane Lucas, Tobias Ahlqvist, Grace P. Robey, Juliana M. S. Dietz, Jule‐Philipp Khairnar, Pankaj V. Maity, Sanjay Williams, Corshai L. Snead, David R. Nelson, Ryan C. Opatz, Till Jamison, Timothy F. Chemistry Research Articles 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. John Wiley and Sons Inc. 2022-07-07 2022-08-22 /pmc/articles/PMC9545417/ /pubmed/35675114 http://dx.doi.org/10.1002/chem.202201311 Text en © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Mear, Sarah Jane
Lucas, Tobias
Ahlqvist, Grace P.
Robey, Juliana M. S.
Dietz, Jule‐Philipp
Khairnar, Pankaj V.
Maity, Sanjay
Williams, Corshai L.
Snead, David R.
Nelson, Ryan C.
Opatz, Till
Jamison, Timothy F.
Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title_full Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title_fullStr Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title_full_unstemmed Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title_short Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline
title_sort diastereoselectivity is in the details: minor changes yield major improvements to the synthesis of bedaquiline
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9545417/
https://www.ncbi.nlm.nih.gov/pubmed/35675114
http://dx.doi.org/10.1002/chem.202201311
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