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Complementation of Biotransformations with Chemical C-H Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals.

Genovino, Julien, Luetz, Stephan, Toure, Bakary-Barry and Sames, Dalibor (2013) Complementation of Biotransformations with Chemical C-H Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals. Journal of the American Chemical Society, 135 (33). pp. 12346-12355. ISSN 0002-7863


It is well-known that metabolism of drugs can produce metabolites with profoundly altered functional parameters such as biological activity, toxicity and clearance rates. Thus, tools that facilitate the rapid identification and synthesis on scale of drug metabolites hold a great potential to facilitate the drug discovery cycle, and guide the selection of clinical candidates. Metabolite identification and scale up is traditionally accomplished via liquid chromatography (LC)/ mass spectrometry (MS/MS), and biotransformations respectively. Challenges in these areas include difficulties in quantitating and elucidating the structure of metabolites in complex biological matrices. In addition, only a small number of human cytochromes P450 (CYP) are currently available recombinantly for biotransformation purposes. To address these major challenges, we aim to develop chemical tools (chemotransformations) to provide rapid access to drug metabolites and related compounds. Towards this goal, we compared biotransformations to existing C-H oxidation toolkit using two marketed drugs (oxcarbazepine 1, naproxen 2) and an early compound hit (phthalazine 3). During the course of these studies, we uncovered that a simple aerobic catalytic protocole (CuI/air) can oxidize tertiary amines (including piperazines, piperidines, 4-amino piperidines, and N,N-dimethylamines) in complex pharmaceuticals to generate formamides, 2,3-diketopiperazines, and C-C/C-N bond fragmentation products. The results also demonstrated that this catalytic system can be used to oxidize subsets of benzylic C-H-containing pharmaceuticals into their corresponding benzyl alcohols/ketones. The oxidized products are drug metabolites or metabolites precursors and can be produced on scale, as exemplified by the oxidation of Imatinib (Gleevec). The operationally practical and simple Cu/air system tolerates a broad range of functional groups and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study begins to chart the basic selectivity rules for specific chemotypes such as complex piperazines and represents a first step towards establishing a chemotransformation toolkit that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.

Item Type: Article
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Keywords: Drug metabolism, bioactivation, secondary drug metabolites, cytochrome P450, C-H oxidation, transition metal catalysis, Cu-mediated aerobic oxidation, tertiary amine oxidation, N-dealkylation
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13


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