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Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline **
Author(s) -
Mear Sarah Jane,
Lucas Tobias,
Ahlqvist Grace P.,
Robey Juliana M. S.,
Dietz JulePhilipp,
Khairnar Pankaj V.,
Maity Sanjay,
Williams Corshai L.,
Snead David R.,
Nelson Ryan C.,
Opatz Till,
Jamison Timothy F.
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202201311
Subject(s) - bedaquiline , yield (engineering) , prioritization , computer science , biochemical engineering , combinatorial chemistry , process engineering , tuberculosis , chemistry , business , engineering , process management , medicine , materials science , mycobacterium tuberculosis , pathology , metallurgy
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.