Emtricitabine Synthesis

Emtricitabine(FTC) is a new nucleoside reverse transcriptase inhibitor,it has the antiviral activity to HIV-1,HIV-2 and HBV.The traditional synthesis methods of emtricitabine were complicated,low productivity,and it was complex to resolute of enantiomers.In this paper,optimal processes were achieved by using glyoxylate as raw material,which reacted with 1(-)menthyl to synthesis chiral intermediate.Emtricitabine was synthesised via four steps:esteration,cyclization,coupling,reduction,and the reaction conditions had also been discussed respectively.The optimum reaction conditions were:the esteration reaction,the solid superacid SO₄^2-/ZrO₂ was used to catalyzed esteration reaction,the yield was up to 78.5%.The cyclization reaction,the reactant molar ratio of {1(-)menthyl glyoxylate hydrate:dithianediol} was 1:1.05,reaction time was 45min,temperture was 80℃. The coupling reaction,the reactant molar ratio of {(2R,5R)-5-hydroxy-[1,3]oxathiola ne-2-carboxylic acid,2S-isopropyl-5R-methyl-1R-cyclohexyl ester:thionyl chloride} was 1:1.05,reaction time was 4 h,reaction temperture was 15℃to get chloride solution;the reactant molar ratio of {cytosine:hexamethyldisilazane} was 1:1.35, maitaining reflux for 2 h to get silylcytosine;then silylcytosine was added to chloride solution and maintained reflux for 6 h,yield of coupling reaction was inhanced by 14%;The reduction reaction,2'S-isopropyl-5'R-menthyl-1 'R-cyclohexyl (2R,5R)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carbo xate oxalate was reducedby KBH₄ in room tempreture,then emtricitabine was recrystallized in ethanol.After optimization,the total yield of emtricitabine was up to 33.4%.The intermediates and emtricitabine were synthesized and their structures were characterized by element analysis,IR,NMR.