Different green synthesis of alkyl esters of acyclovir (acyclovir prodrugs) is described. Hexanoic, decanoic, dodecanoic and tetradecanoic acyclovir esters were synthesized reacting acyclovir and the respective acid anhydride in dimethyl sulfoxide (DMSO), in solvents from renewable sources and without solvent (T°03؍C). Yields in prodrugs after 10 min of reaction were Ͼ Ͼ95% using DMSO as solvent. The purification methodology was very simple, shorter and greener than previously described. The biosolvent, N,N-dimethylamide of decanoic acid, let us to obtain Ͼ Ͼ95% yield at 24 h. This oily biosolvent is not dermotoxic and the reaction crude can directly be used in topic formulations. Syntheses without solvent proceeded successfully for acyclovir esters. Indeed, dodecanoate and tetradecanoate yielding Ͼ Ͼ98% conversion of reactants in 30 min. In spite of requiring mild temperature (65°C), substrate molar ratios were lowered to 1 : 1, thus conducing to a more efficient use of raw materials. The synthetic procedures were scaled up to a 300 g batch (yield 98-99% isolated ester). These esters can be used as acyclovir prodrugs in topic formulations. The esters release from an oil/water micro-emulsion and a hydrogel formulation were tested with good results.
Different methods are described for the synthesis of acyclovir prodrugs of type (III). The synthesis can be performed in DMSO or in decanoic acid N,N-dimethylamide. With long--chain fatty acid anhydrides (C12 and C14) the synthesis can also be performed under solventless conditions. The synthesis of (IIIb) in DMSO is also performed on a 300g-scale. -(DE REGIL-HERNANDEZ, R.; MARTINEZ-LAGOS, F.; RODRIGUEZ-BAYON, A.; SINISTERRA*, J.-V.; Chem.
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