The condensation of 2-(acetoxymethoxy)-1,3-bis(benzyloxy)propane (XIV) with N2-acetylguanine (XV) by means of hexamethyldisilazane (HMDS) and trifluoromethanesulfonic acid gives the N2-acetyl-O,O'-dibenzylganciclovir (XVI), which is selectively monodebenzylated with either H2 over Pd/C in methanol or cyclohexene and Pd(OH)2 in refluxing ethanol, yielding intermediate (XVII), which by deacetylation with NH4OH in methanol affords mono-O-benzylganciclovir (XVIII). The condensation of (XVIII) with N-benzyloxycarbonyl-L-valine (XIX) by means of DCC in dichloromethane gives the expected valine ester (XX), which is finally debenzylated with H2 over Pd/C in methanol as before.
The silylation of ganciclovir (I) with TMSCl and imidazole in DMF gives the N2-silylated compound (II), which by condensation with N-benzyloxycarbonyl-L-valine-N-carboxyanhydride (III) and subsequent treatment with 3M HCl yields the monoprotected valganciclovir derivative (IV). Finally, this compound is submitted to hydrogenolysis with H2 over Pd/C in methanol/HCl.
The condensation of ganciclovir (I) with the activated L-valine derivative (III) by means of triethylamine in DMF gives the O,O'-bis(valyl)ganciclovir derivative (V), which by selective removal of one of the L-valine groups with propylamine in hexane yields the previously reported monoprotected valganciclovir derivative (IV).
The reaction of ganciclovir (I) with trimethyl orthoformate and TFA in DMF gives the cyclic orthoester (XI), which is treated with formic acid in DMF/water to yield ganciclovir O-monoformate (XII). The condensation of (XII) with N-benzyloxycarbonyl-L-valine-N-carboxyanhydride (III) by means of triethylamine in DMF affords the expected monovalinate (XIII), which is deformylated with HCl in methanol/dichloromethane to give the previously reported monoprotected valganciclovir derivative (IV). The preceding reaction sequence can also be performed by substituting trimethyl orthoformate with other orthoesters such as benzyl orthoformate, ethyl orthoacetate, methyl orthoacetate or ethyl orthopropionate.
The reaction of ganciclovir (I) with trityl chloride in DMF in the presence of triethylamine and DMAP gives the N,O-bis(trityl) compound (VI), which is condensed with the activated L-valine derivative (III) by means of triethylamine in DMF/toluene to yield the expected valine ester (VII). Finally, the trityl groups of (VII) are removed with TFA in trifluoroethanol to afford the previously reported monoprotected compound (IV). The condensation of the tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine (VIII) by means of DCC in dichloromethane gives the expected valine ester (IX), which is finally deprotected with TFA in dichloromethane. The valine ester (IX) can also be obtained by condensation of tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine-N-carboxyanhydride (X) by means of triethylamine in DMF.
The condensation of 1-acetoxy-2-(acetoxymethoxy)-3-(benzyloxy) propane (XXI) with guanine (XXII) by means of HMDS and trifluoromethanesulfonic acid gives O-acetyl-O'-benzylganciclovir (XXIII), which is deacetylated with NaOH in methanol to yield the previously reported mono-O-benzylganciclovir (XVIII). The preceding reaction sequence can also be performed by using 1-(benzyloxy)-2-(propionyloxymethoxy)-3-(propionyloxy)propane (XXIV) instead of compound (XXI), yielding intermediate (XXV) and finally the previously reported mono-O-benzylganciclovir (XVIII).