Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a cytidine analog which is used for the treatment of tumors caused by several types of cancer. Our earlier studies with 4-N-[11-(methanesulfoxy)undecanyl] gemcitabine derivative showed this compound was compatible with 18F-fluorination protocols; but displayed elimination of 18F during in vivo PET imaging studies. In order to avoid these later limitations, and further facilitate fluorination protocols, we designed and synthesized a 4-N-alkyl gemcitabine analog containing a lipophilic 11-carbon chain with a β-keto tosylate moiety (e.g. 2). Synthesis began by displacement of p-toulenesulfonylamino in 4-N-tosylgemcitabine with 1-amino-10-undecene to yield 4-N-alkenyl gemcitabine analog 1. Protection of the sugar hydroxyls, followed by oxidation of the alkene modality using OsO4/ NMO afforded the corresponding diol. The regioselective tosylation of the latter at the primary hydroxyl (TsCl/Et3N) followed by oxidation of the secondary alcohol with Collin’s reagent yielded β-keto tosylate analog 2. Fluorination of 2 with KF and Kryptofix 2.2.2. or 18-Crown-6 (MeCN/75 oC/1h), followed by deprotection with NH3/MeOH (0 oC/30min) gave the fluorinated 4-N-alkyl gemcitabine analog 3. These fluorination/deprotection conditions are compatible with the general radiosynthetic protocols for 18F-labeling.

Synthesis of 4-N-alkyl gemcitabine analog bearing β-keto tosylate moiety suitable for 18F-labeling

253rd National Meeting (2017)

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