ABSTRACT
Most of the active pharmaceutical ingredients like Metoprolol are oxidatively metabolized by liver enzymes, such as Cytochrome P450 monooxygenases into oxygenates and therefore hydrophilic products. It is of utmost importance to identify the metabolites and to gain knowledge on their toxic impacts. By using electrochemistry, it is possible to mimic enzymatic transformations and to identify metabolic hot spots. By introducing charged-tags into the intermediate, it is possible to detect and isolate metabolic products. The identification and synthesis of initially oxidized metabolites are important to understand possible toxic activities. The gained knowledge about the metabolism will simplify interpretation and predictions of metabolitic pathways. The oxidized products were analyzed with high performance liquid chromatography-mass spectrometry using electrospray ionization (HPLC-ESI-MS) and nuclear magnetic resonance (NMR) spectroscopy. For proof-of-principle, we present a synthesis of one pyridinated main oxidation product of Metoprolol.
Subject(s)
Metoprolol/chemistry , Metoprolol/metabolism , Pyridinium Compounds/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Alkylation , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme System/metabolism , Electrochemical Techniques , Hydroxylation , Oxidation-Reduction , Pyridines/chemistry , Pyridinium Compounds/isolation & purification , Signal TransductionABSTRACT
1,4-Benzoxazin-3-ones are important structural motifs in natural products and bioactive compounds. Usually, the synthesis of benzoxazinones requires transition-metal catalysts and pre-functionalized substrates such as aryl halides. However, the anodic C-H amination of phenoxy acetates offers a very efficient and sustainable access to these heterocycles. The presented electrochemical protocol can be applied to a broad scope of alkylated substrates. Even tert-butyl moieties or halogen substituents are compatible with this versatile method.
