Improved Synthesis and Isolation of Bedaquiline

Hlengekile Lubanyana; Per I Arvidsson; Thavendran Govender; Hendrik G Kruger; Tricia Naicker

doi:10.1021/acsomega.9b04037

Improved Synthesis and Isolation of Bedaquiline

ACS Omega. 2020 Feb 17;5(7):3607-3611. doi: 10.1021/acsomega.9b04037. eCollection 2020 Feb 25.

Authors

Hlengekile Lubanyana¹, Per I Arvidsson^{1

2}, Thavendran Govender¹, Hendrik G Kruger¹, Tricia Naicker¹

Affiliations

¹ Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4000, South Africa.
² Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine, and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.

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).