A novel approach to the synthesis of lipophilic thymidinemonophosphoglucopyranosides as drug delivery systems

Article abstract of DOI:10.1016/0008-6215(96)00042-0

The paper describes the synthesis of the hexadecyl phosphotriesters of thymidine 3′-(5′-deoxythymidin-5′-yl phosphate), thymidine 5′-(5′-deoxythymidin-5′-yl phosphate), thymidine 5′-(3′,5′-dideoxythymidin-5′-yl phosphate), thymidine 3′-[(methyl 6-deoxy-α-D-glucopyranosid-6-yl) phosphate], and thymidine 5′-[(methyl 6-deoxy-α-D-glucopyranosid-6-yl) phosphate]. The novel approach is based on the condensation of unprotected nucleosides or pyranosides with the lipophilic phosphodiesters 5′-O-dimethoxytritylthymidine 3′-(hexadecyl phosphate) and 3′-O-dimethoxytritylthymidine 5′-(hexadecyl phosphate) which were obtained in satisfactory yield from hexadecyl phosphorodichloridite and 5′-O-dimethoxytrityl-or 3′-dimethoxytrityl-thymidine. The latter was prepared in high yield from 5′-O-(4-nitrobenzoyl)thymidine, obtained from thymidine, 4-nitrobenzoic acid, and bis(2-oxooxazolidin-3-yl)phosphinic chloride, by a one-pot procedure. The introduction of the aliphatic chain in the early stage of the synthesis prevents the alkylation of the nucleobases and allows a regioselective phosphorylation of unprotected nucleosides and pyranosides.