Bicyclic enol compound (I) was phosphorylated by means of diphenyl phosphorochloridate and diisopropylethylamine, and the resulting enol phosphate was displaced with thioacetic acid yielding thioacetate ester (II). Cleavage of the phenylacetamido group of (II) to afford amine (III) was then effected by treatment with PCl5 and pyridine, followed by quenching with isobutyl alcohol. On the other side, thiazole (IV) was chlorinated with N-chlorosuccinimide to provide the 5-chlorothiazole (V). Protection of the amino group of (V) with di-tert-butyl dicarbonate, followed by ester hydrolysis gave (VI). The oximino group of (VI) was then protected as the O-trityl derivative (VII) by treatment with triphenylmethyl chloride. Coupling of carboxylic acid (VII) with amine (III) employing POCl3 and pyridine provided amide (VIII). Optionally, hydrolysis of the thioacetate ester using morpholine and pyridine, followed by S-alkylation with chloroiodomethane furnished the chloromethylsulfanyl derivative (IX).
In a related procedure, chloromethylsulfanyl derivative (IX) was condensed with 2,4-diamino-6-mercaptopyrimidine (XI) to give thioacetal (XIII), which was then deprotected with trifluoroacetic acid-promoted cleavage of Boc, trityl and benzhydryl protecting groups of (XIII) yielded the title compound.
Thioacetate ester (VIII) was hydrolyzed to thiol (X) by treatment with morpholine and triethylamine. The iodomethylsulfanyl pyrimidine (XII) was prepared by alkylation of 2,4-diamino-6-mercaptopyrimidine (XI) with bromochloromethane, followed by displacement of the chlorine with NaI in acetone. Alkylation of thiol (X) with iodide (XII) gave rise to thioacetal (XIII). Finally, trifluoroacetic acid-promoted cleavage of Boc, trityl and benzhydryl protecting groups of (XIII) yielded the title compound.