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

The paper describes the synthesis of the hexadecyl phosphotriesters of thymidine 3'-(5'-deoxythymidin'5-yl phosphate), thymidine 5'-(5'-deoxyrhymidin-5'-yl phosphate), thymidine 5'- (3',5'-dideoxythymidin-5'-yl phosphate). thymidine 3'-[(methyl 6-deoxy-alpha-D-glucopyranosid-6-yl) phosphate], and thymidine 5'-[(methyl 6-deoxy-alpha-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. (C) 1996 Elsevier Science Ltd.