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An efficient two-step method for the synthesis of 2-bromo-4-nitroimidazole, 6, a key building block for nitroimidazole drugs, has been developed. The synthesis involves dibromination of 4-nitroimidazole 10 followed by selective debromination using in situ reductive deiodination strategy. The reactions are facile, safe, and easy to scale up. The large-scale applicability of this improved method was tested by conducting the reactions on kilogram scale to produce the desired product in high yield and quality.

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A process suitable for kilogram-scale synthesis of (2R)-2-methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole (DNDI-VL-2098, 2), a preclinical drug candidate for the treatment of visceral leishmaniasis, is described. The four-step synthesis of the target compound involves the Sharpless asymmetric epoxidation of 2-methyl-2-propen-1-ol, 8. Identification of a suitable synthetic route using retrosynthetic analysis and development of a scalable process to access several kilograms of 2 are illustrated. The process was simplified by employing in situ synthesis of some intermediates, reducing safety hazards, and eliminating the need for column chromatography. The improved reactions were carried out on the kilogram scale to produce 2 in good yield, high optical purity, and high quality.