Synthesis of potential drug metabolites by a modified Udenfriend reaction

• Published in: Tetrahedron letters Vol. 52; no. 7; pp. 749 - 752
• Main Authors: Slavik, Roger, Peters, Jens-Uwe, Giger, Rudolf, Bürkler, Markus, Bald, Eric
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 16.02.2011; Elsevier
• Subjects: Accessibility; Aromatic hydroxylation; Biomedical materials; Biomimetic oxidation; chemical structure; Chemistry; Chemistry, Organic; chlorpromazine; derivatization; Diltiazem; Drug discovery; Drugs; hydroxylation; In vivo testing; In vivo tests; Metabolites; oxidation; Physical Sciences; propranolol; Science & Technology; Synthesis (chemistry); Aromatic hydroxylation; Drug discovery; Metabolites; Biomimetic oxidation; CLOZAPINE; RAT; DEMETHYLATION; MIST; HYDROGEN-PEROXIDE; FENTON REAGENT; MODEL; SELECTIVITY
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2010.12.014

The scope and the limitations of a modified Udenfriend reaction for the one-step synthesis of potential drug metabolites were explored. Several drugs (clozapine, chlorpromazine, imipramine, buspirone, diltiazem, and propranolol) were subjected to modified Udenfriend conditions (Fe 2+/Mn 2+/EDTA/ascorbic acid/O 2). From each reaction, one to four oxidation products were obtained in 1–8% overall yield. Many of these products (9 out of 14) have been reported to be metabolites of the parent drugs in vivo. The products resulted mainly from aromatic hydroxylation, and are not readily accessible by conventional synthesis. Thus, the described reaction may be useful in drug discovery whenever a facile synthetic access is more important than high yields (e.g., for a fast derivatisation of compounds or the preparation of metabolites). Poorly water-soluble compounds cannot be converted, which is an important limitation of this method.