Collect. Czech. Chem. Commun. 1997, 62, 1128-1135

Preparation of Thymidine-4'-C-carboxylic Acid and Its Derivatives

Hubert Hřebabecký and Antonín Holý

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,166 10 Prague 6, Czech Republic


3',5'-Di-O-benzoyl-4'-C-hydroxymethylthymidine (3) was prepared in four steps from 3'-O-(tert-butyldimethylsilyl)-4'-C-hydroxymethylthymidine (1). Oxidation of 3 with pyridinium dichromate afforded 3',5'-di-O-benzoylthymidine-4'-C-carboxylic acid (4) which on debenzoylation gave free thymidine-4'-C-carboxylic acid, (3R,2S,5R)-3-hydroxy-2-hydroxymethyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid, (5). Esterification of acid 5 with diazomethane afforded the methyl ester 6. Its isopropyl ester 7 was obtained by transesterification of the methyl ester 6. Reaction of ester 6 with ammonia and hydrazine led to the respective amide 8 and hydrazide 9. Upon reaction with 1,1'-carbonyldiimidazole, the protected acid 4 was converted into the corresponding imidazolide 11, which, without isolation, was treated with glycinamide, dimethylamine and aminoethanol to give aminocarbonylmethylamide 12a, N,N-dimethylamide 13a and hydroxyethylamide 14a, respectively. The free amides 12b, 13b and 14b were obtained by methanolysis of corresponding benzoates with methanolic sodium methoxide. Neither of the prepared compounds exhibited significant activity against HIV.

Keywords: (3R,2S,5R)-3-Hydroxy-2-hydroxymethyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid; Thymidine-4'-C-carboxylic acid.