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 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.
A new synthesis of A-515-U has been reported. The compound can be synthesized in two similar ways: 1) The reaction of 9-(2-acetoxyethoxymethyl)-2-(acetylamino)-6,9-dihydro-1H-purin-6-one (I) with POCl3 and 2,4,6-trimethylpyridine in refluxing acetonitrile gives 9-(2-acetoxyethoxymethyl)-2-(acetylamino)-6-chloro-9H-purine (II), which is dechlorinated with formic acid - triethylamine and Pd/C in refluxing acetone, yielding 9-(2-acetoxyethoxymethyl)-2-(acetylamino)-9H-purine (III). Finally, this compound is deacetylated in water. 2) Purine (I) is partially deacetylated with triethylamine in refluxing ethanol to give 9-(2-acetoxyethoxymethyl)-2-amino-6,9-dihydro-1H-purin-6-one (IV), which is treated with POCl3 as before to yield the chloropurine (V). The dechlorination of (V) with HCO2H as before or with ammonium formate - Pd/C affords 9-(2-acetoxyethoxymethyl)-2-amino-9H-purine (VI), which is finally deacetylated with methylamine as before.