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Improved Synthesis and Isolation of Bedaquiline.

ABSTRACT: Bedaquiline (BDQ) is the most critical pharmaceutical in the world for treating multidrug-resistant Mycobacterium tuberculosis. Despite it being highly effective, BDQ asymmetric synthesis remains a challenge. Herein, the influence of chiral bases, namely, bis(1-phenylethyl)amine, bisoxazoline, and sparteine on the diastereoselective lithiation reaction to obtain BDQ was investigated. The highest diastereoselective ratio (dr) emerged as 90:10 from the (+)-bis[(R)-1-phenylethyl] lithium amide. This is a significant improvement from the 50:50 dr achieved from the commercial synthesis. Thereafter, the desired (90:10 RS, SR) diastereomeric mixture was easily isolated via a gravity column and subjected to chiral supercritical fluid chromatography (SFC) to access the desired enantiomer (1R, 2S)-BDQ. The advantages of this procedure are enhanced diastereoselection as well as a greener, faster way to achieve excellent enantioseparation (up to 1.0 g scale).

SUBMITTER: Lubanyana H

PROVIDER: S-EPMC7045498 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Improved Synthesis and Isolation of Bedaquiline.

Lubanyana Hlengekile H Arvidsson Per I PI Govender Thavendran T Kruger Hendrik G HG Naicker Tricia T

ACS omega 20200217 7

Bedaquiline (BDQ) is the most critical pharmaceutical in the world for treating multidrug-resistant <i>Mycobacterium tuberculosis</i>. Despite it being highly effective, BDQ asymmetric synthesis remains a challenge. Herein, the influence of chiral bases, namely, bis(1-phenylethyl)amine, bisoxazoline, and sparteine on the diastereoselective lithiation reaction to obtain BDQ was investigated. The highest diastereoselective ratio (dr) emerged as 90:10 from the (+)-bis[(<i>R</i>)-1-phenylethyl] lith ...[more]

PMID: 32118176

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