Synthesis of 5-substituted 2'-deoxyuridines

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Abstract
A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2''-deoxyuridine and its dithiolane derivative were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followed by saponification of the protective groups. 5-Acetyl-2''-deoxyuridine was prepared in the same way from 5-acetyluracil. Treatment of the diester of 5-allyl-2''-deoxyuridine with m-chloroperbenzoic acid gave the corresponding epoxide. Dimethylamine removed the ester groups and opened the epoxide to give the amino alcohol. The diester of 5-chloromethyl-2''-deoxyuridine (27) treated with methanol or sodium azide gave 5-methoxymethyl- and 5-azidomethyl- 2''-deoxyuridines. Compound 27 also was converted to 5-iodoacetamidomethyl-2''-deoxyuridine by treatment with ammonia, chloroacetyl chloride, base saponification and finally sodium iodide. [Antineoplastic activity is discussed.].