An efficient and selective process for the synthesis of acyclovir has been published: The reaction of guanine (I) with refluxing hexamethyldisilazane (HMDS) (II) by means of trifluoromethanesulfonic acid, elimination of the HMDS in excess and condensation of the resulting product with refluxing 1,3-dioxolane (III) gives 9-[2-(trimethylsilyloxy)ethoxymethyl]guanine (IV), which is finally hydrolyzed with refluxing acetic acid/water.
The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with NaNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.
The condensation of guanine (IX) with refluxing hexamethyldisilazane followed by reaction with 1-benzoyloxy-2-chloromethoxyethane (IV) by means of triethylamine in refluxing benzene gives 9-(2-benzoyloxyethoxymethyl)guanine (X), which is finally hydrolyzed with ammonia in methanol at 80 C in a pressure vessel.
The condensation of 2-amino 6 chloropurine (I) with 2-benzyioxyethoxymethyl chloride (II), by means of K2CO3 in DMF gives 2-amino-6 chloro 9-(2 benzyloxyethoxymethyl)purine (III), which is then dechlorinated by reduction with H2 over Pd/C in ethanol containing triethylamine.
The acetylation of guanine (I) or guanosine (II) with acetic anhydride gives the diacetyl guanine (III), which is condensed with 1,4-diacetoxy-2-oxabutane (IV) by means of TsOH to yield N,O-diacetyl acyclovir (V). Finally, this compound is deacetylated with NH3, NaOH or pyrrolidine at room temperature, or also with refluxing glycol.
The reaction of 1,3-dichloro-2-propanol (I) with Bn-ONa gives 1,3-dibenzyloxy-2-propanol (II), which by reaction with paraformaldehyde and HCl is converted into the chloromethyl ether (III). The reaction of (III) with potassium acetate affords the acetoxymethyl ether (IV), which is condensed with diacetylguanine (V) by means of TsOH to provide fully protected ganciclovir (VI). Finally, this compound is debenzylated to (VII) with Pd(OH)2/cyclohexene and deacetylated with ammonia in methanol.
The reaction of 4-(chloromethyl)-1,3-dioxolane (I) with Ac2O, HOAc and ZnCl2 gives the diacetoxy compound (II), which is treated with KOAc to yield the triacetoxy compound (III). The condensation of (III) with diacetyl guanine (IV) by means of ethylsulfonic acid affords the triacetyl ganciclovir (V), which is finally deacetylated with methylamine in methanol.