Synthesis of Doxycycline-[(CD3)-C-13]


Bordia, T., McGregor, M., Papke, R. L., McIntosh, M. J., Decker, M. W., & Quik, M. (2014, 15-19 November). The ?7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in parkinsonian rats. Paper presented at Neuroscience 2014, Washington, DC.


Doxycycline is a tetracycline antibiotic that is used to treat a wide variety of infections. A mass spectrometry (MS) analytical standard with M + 4 was prepared to support pharmacology and toxicology. Our approach was to first N-demethylate doxycycline and re-methylate using stable isotope labeled methyl-[13CD3] iodide to produce doxycycline-[13CD3]. An iron mediated Polonovsky reaction efficiently N-demethylated doxycycline. In this process, doxcycline was oxidized to the N-oxide using m-CPBA. The hydrochloride salt of the tertiary N-oxide was treated with Fe(0)/FeCl3 catalyst yielding the N-demethylated product. Isolated pure demethyldoxycycline was re-methylated using diisopropyl azodicarboxylate (DIAD), polymer-supported triphenylphosphine and methyl-[13CD3] iodide. We have synthesized labeled doxycycline with an isotopic purity of 99% using this methodology.

Keywords: MS internal standard; antibiotic; demethylation; doxycycline.

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