Synthesis of Fexinidazole

Fexinidazole is synthesised using nitroimidazole as a raw material by chemical reaction. The specific synthesis steps are as follows:

The synthesis of fexinidazole started with the methylation of nitroimidazole (2.1) using dimethyl sulfate in dioxane to obtain intermediate 2.2 in 82% yield. Methylated imidazole 2.2 was treated with formaldehyde in dimethyl sulfoxide to give the corresponding imidazolyl methanol derivative 2.3 in 62% yield. Treatment of 2.3 with thionyl chloride in chloroform provided the corresponding 2- chloromethyl-1-methyl-5-nitroimidazole 2.4, which was further coupled with 4-methylmercaptophenol (2.5) in the presence of K2CO3 in acetone to give "wet" fexinidazole HCl (2.6). Upon neutralization with 25% aqueous ammonia, fexinidazole free base was obtained in 65% yield over 3 steps.

Introduction of Fexinidazole

Fexinidazole, a 2-substituted-5- nitroimidazole antiprotozoal agent, was originally synthesized and disclosed by Hoechst AG (now part of Sanofi) in the 1970s. In 2005, a collaborative screening campaign of nitroheterocyclic compounds by the Drugs for Neglected Diseases initiative and Sanofi identified that the compound has activity against Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. This led to the rediscovery of fexinidazole as a promising candidate for the treatment of human African trypanosomiasis (HAT), commonly known as sleeping sickness.

In November 2018, the European Medicines Agency (EMA) adopted a positive opinion of fexinidazole for the treatment of both stage-1 (hemolymphatic) and stage-2 (meningoencephalitic) HAT in adults and children. As the first all-oral treatment for HAT, the World Health Organization added fexinidazole to the essential drugs list in 2019. In July 2021, the USFDA approved fexinidazole for treatment of HAT in patients 6 years of age and older and weighing at least 20 kg.