Selective Reduction of N-Oxides to Amines: Application to Drug Metabolism

Phase I oxidative metabolism of nitrogen-containing drug molecules to their corresponding N-oxides is a common occurrence. There are instances where liquid chromatography/tandem mass spectometry techniques are inadequate to distinguish this pathway from other oxidation processes, including C-hydroxylations and other heteroatom oxidations, such as sulfur to sulfoxide. Therefore, the purpose of the present study was to develop and optimize an efficient and practical chemical method to selectively convert N-oxides to their corresponding amines suitable for drug metabolism applications. Our results indicated that efficient conversion of N-oxides to amines could be achieved with TiCl3 and poly(methylhydrosiloxane). Among them, we found TiCl3 to be a facile and easy-to-use reagent, specifically applicable to drug metabolism. There are a few reports describing the use of TiCl3 to reduce N-O bonds in drug metabolism studies, but this methodology has not been widely used. Our results indicated that TiCl3 is nearly as efficient when the reductions were carried out in the presence of biological matrices, including plasma and urine. Finally, we have shown a number of examples where TiCl3 can be successfully used to selectively reduce N-oxides in the presence of sulfoxides and other labile groups.