Dimethyl Sulfoxide → HCID 453631, compound

A number of 4′-C-branched nucleosides have been reported in O-Yang C., Wu, H. Y., Fraser-Smith, E. B., Walker, K. A. M. Tetrahedron Lett.s, 1992, 33, 37-40. This invention provides procedures for preparation of many new 4′-C-branched nucleosides. Preparation of 4′-C-branched thymidines is shown in Reaction schemes 3, 4, and 5 (FIGS. 4, 5, 6, and 7, respectively). These procedures may be readily adapted for the synthesis of other nucleosides of the invention, including embodiments of the invention in which the nucleosides comprise a base other than thymine. Compound 16, prepared from thymidine, was treated with dimethoxytrityl chloride to give Compound 17. t-Butyldimethylsilyl (TBDMS) group of Compound 17 was removed by treatment with TBAF to give Compound 18, which was oxidized to an aldehyde, Compound 19 by treatment with dimethyl sulfoxide, DCC, trifluoroacetic acid, and pyridine. Compound 19 was converted to Compound 20, a 4′-C-hydroxy-methylthymidine derivative, by a procedure similar to those as described (a. O-Yang C., Wu, H. Y., Fraser-Smith, E. B., Walker, K. A. M. Tetrahedron Letts,1992,33, 37-40; b. Jones, G. H., Taniguchi, M., Tegg, D., Moffatt, J. G. J. Org. Chem. 1979, 44, 1309-17). Dimethoxytrityl group of Compound 20 was removed with 80% acetic acid to give Compound 21, 4′-C-hydroxymethyl-thymidine. Selective benzoylation of Compound 21 with benzoyl anhydride affords Compound 22, 3′- and 5′-hydroxyl groups of which were protected with tetrahydropyranyl (THP) by reaction of Compound 22 with dihydropyran in the presence of toluenesulfonic acid in dichloromethane. The resulting Compound 23 was treated with aqueous sodium hydroxide to give Compound 24, which was reacted with methyl iodide in the presence of sodium hydroxide at 0° C. to give a 4′-C-methoxy-methylthymidine derivative, Compound 25. Removal of THP protecting groups of Compound 25 afforded Compound 26, 4′-C-methoxymethylthymidine. For some reactions TBDMS protecting group is preferred to THP because of formation of diastereomers caused by THP. Thus, treatment of Compound 22 with t-butyldimethylchlorosilane afford 3′, 5′-O-(bis-TBDMS) thymidine derivative, Compound 27. Removal of benzoyl group with ethylenediamine at 50° C. afforded Compound 28, which reacted with trifluoromethanesulfonic anhydride and pyridine in dichloromethane to give a triflate, Compound 29. Reaction of Compound 29 with ammmonia in dioxane afforded a 4′-C-amino-methylthymidine derivative, Compound 30. Reaction of Compound 29 with sodium azide in DMF afforded a 4′-C-azidomethyl-thymidine derivative, Compound 31. Removal of TBDMS protecting groups of Compound 30 and 31 afforded Compound 32 and 33, 4′-C-aminomethylthymidine and 4′-C-azidomethylthymidine, respectively. Amino group of Compound 33 was protected with trifluoroacetyl group to give Compound 34. Reaction of Compound 32 and 34 with dimethoxytrityl chloride in pyridine afforded Compound 35 and 36, respectively. Compound 35 and 36 were converted to the corresponding phosphoramidites, Compound 37 and 38, respectively, by treatment with 2-cyanoethyl-N, N-diisopropylchlorophosphor-amidite.

1. customt-Butyldimethylsilyl (TBDMS) group of Compound 17 was removed by treatment with TBAF
2. customto give Compound 18, which
3. customDimethoxytrityl group of Compound 20 was removed with 80% acetic acid

ORD record

ord-a4552c26344d42eb874953b4f25c2e18

Source dataset

uspto-grants-2001_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06191266B1