Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol

Tobias Lucas; Jule-Philipp Dietz; Flavio S P Cardoso; David R Snead; Ryan C Nelson; Kai O Donsbach; B Frank Gupton; Till Opatz

doi:10.1021/acs.oprd.3c00187

Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol

Org Process Res Dev. 2023 Sep 5;27(9):1641-1651. doi: 10.1021/acs.oprd.3c00187. eCollection 2023 Sep 15.

Authors

Tobias Lucas¹, Jule-Philipp Dietz¹, Flavio S P Cardoso², David R Snead², Ryan C Nelson², Kai O Donsbach², B Frank Gupton², Till Opatz¹

Affiliations

¹ Department of Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz, Germany.
² Department of Chemical and Life Sciences Engineering, Virginia Commonwealth University, Richmond, Virginia 23284, United States.

Abstract

An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four different protecting groups on the glycidol moiety were investigated for their technical feasibility and ability to suppress side reactions. Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.