Synthesis of the stable isotope labeled antiviral nucleoside analog [8-¹³C-7,9-¹⁵N₂]-ganciclovir

Ganciclovir, a nucleoside analog of 2′-deoxyguanosine, is a drug used in suicide gene therapy for the treatment of mesothelioma. We required a stable isotope analog of ganciclovir for use in pharmacokinetic studies in order to monitor the systemic exposure of patients to the drug. Therefore, a facile and efficient synthesis of [8-¹³C-7,9-¹⁵N₂]- ganciclovir, was devised. The synthesis was achieved in 4 steps with 25% total yield using commercially-available [8-¹³C-7,9-¹⁵N ₂]-guanine, without the need for purification of intermediates. The key step of the synthesis involved the coupling of [8-¹³C-7,9- ¹⁵N₂]-guanine with 3-propionyloxy-2-propionyloxy- methoxypropyl propionate. The latter was synthesized from a commercially available dichlorohydrin. Each step of the reaction could be easily monitored by liquid chromatography-mass spectrometry. The structure of the labeled ganciclovir was confirmed using ¹H, ¹³C, and ¹⁵N nuclear magnetic resonance spectroscopy.