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Reaction of methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-glucopyranuronate with 3′-deoxy-3′-fluorothymidine in the presence of trimethylsilyl trifluoromethanesulfonate gave (2R,3R,4S,5S,6S)-2-(((2R,3S,5R)-3-fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, which was hydrolysed to 3′-deoxy-3′-fluorothymidine-5′-glucuronide. Analysis of this reference standard by high performance liquid chromatography enabled the identification of [18F]3′-deoxy-3′-fluorothymidine-5′-glucuronide in blood samples from six human patients who had been administered [18F]3′-deoxy-3′-fluorothymidine.

The study is aimed at the analysis and identification of radiochemical and chemical impurities present in [18F]FLT synthesized by a simplified combination-column purification procedure, instead of the currently used HPLC purification. HPLC analysis of the final product showed an anionic radioactive byproduct, which was established as [18F]4-FBSA. The identity of the product was also confirmed by the radiofluorination of nosyl chloride. Mass spectrum analysis of both a decayed sample of [18F]FLT and fluorinated nosyl chloride showed a major peak at 242. We have also investigated the possible interference of this byproduct during PET-imaging in rabbits.

A series of pro-nucleotide phosphoramidates and phosphorodiamidates of the antiviral lead compound 3′-deoxy-3′-fluorothymidine (FLT) have been designed and synthesized. In vitro antiretroviral and cytostatic studies revealed potent (sub-micromolar) inhibition of HIV-1 and HIV-2 replication, with retention of activity in thymidine kinase-negative cell models, as predicted by the ProTide concept.

A convenient preparation of α- and β-anomers of 1,5-di-O-benzoyl-2,3-dideoxy-3-fluoro-D-erythro-pentofuranose is described. Each anomer is studied as the glycosylating agent in the reaction with bis-trimethylsilylated thymine in the presence of trimethylsilyl triflate. Under optimum conditions, 2',3'-dideoxy-3'-fluorothymidine (FLT) and its α-anomer are isolated in 64 and 25% yields, respectively

The 5-OH-protected methyl glycosides 2 and 3 were epimerized to give the corresponding epimers 6 and 7 via an oxidation-reduction procedure. Reaction of 6 with diethylamino-sulfur trifluoride (DAST) afforded the fluoro sugar 8, which was coupled with thymine to give 3′-deoxy-3′-fluorothymidine (12) after deprotection with saturated ammonia in methanol.

The use of methyl 5-0- tert -butyldiphenylsilyl-2-deoxy-α , β -D- threo -pentofuranoside, prepared from D-xylose,as a divergent intermediate for the synthesis of 3'-substituted-2',3'-dideoxynucleosides is illustrated by its conversion into 3'-azido-3'-deoxythymidine, 3'-deoxy-3'-fluorothymidine and 3'-cyano-3'-deoxythymidine.

Stereospecific synthesis of (−)-carba-3′-deoxy-3′-fluorothymidine (−)- 11 is reported from the protected (−)-carbocyclic 3′-epi-thymidine (−)- 7 using diethylaminosulfur trifluoride. Under the conditions used, extensive dehydration of the blocked precursor into 10 and formation of the 4′-fluoro analogue ( 9 ) were also observed. An attempted simplification of our methodology based on (+)-(1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one failed, but a novel cyclopentane ( 2 ) ring expansion to tetrahydropyran ( 18 ) was discovered.

(−)-Carba-2′,3′-dideoxythymidine 5a and (−)-carba-2′,3′-dideoxy-3′-fluorothymidine 5b were, prepared from (±)- endo -5-norbornen-2-o1 using both enzymatic and chemical procedures.