Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 28, Issue 47, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202201311
Keywords
bedaquiline; continuous flow; diastereoselectivity; lithiation; nucleophilic addition
Categories
Funding
- Bill and Melinda Gates Foundation (BMGF) through the Medicines for All Institute (M4ALL)
- National Science Foundation Graduate Research Fellowship [1745302]
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This study improved the synthesis method of bedaquiline, increasing the yield and reducing the cost, making this crucial medication more accessible to a larger number of patients.
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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