5-(2-Hydroxyethyl)uracil

Synthesis

89532-90-1

23956-12-9

The general procedure for the synthesis of 5-(2-hydroxyethyl)pyrimidine-2,4(1H,3H)-diones from the compound (CAS: 89532-90-1) is as follows: first, based on the modification of the 5-position of uracil, referring to the literature method (JD Fissekis, A. Myles, GB Brown, J. Org. Chem. 1964, 29, 2670 ) for large-scale preparation. The procedure consisted of the preparation of the sodium salt 26 by formylation of 25 g of γ-butyrolactone with methyl formate, followed by reaction with a urea derivative 27 to give hydroxyethyluracil 28 by cyclization (Scheme 1). Next, hydroxyethyluracil 28 was methylated with methanesulfonyl chloride in pyridine to give compound 29 (JD Fissekis, F. Sweet, J. Org. Chem. 1973, 38, 264). Innovative steps included the reaction of compound 29 with sodium azide in DMF to produce azide 30, followed by reduction with triphenylphosphine in pyridine to give aminoethyluracil 31. Finally, the amino functional group in 31 was protected using N-ethoxycarbonylphthalimide (Scheme 2). Then, nucleotidylation of ribosyl tetrabenzoate 33 with N-phenylformylaminoacetate 32 afforded ribosyl trisbenzoate 34 in high yield.The coupling constants between H-C(1') and H-C(2') by J = 9.5 Hz clearly showed that the heterojunction center of the pyranose ring was in the β-configuration. Subsequently, the benzoate protecting group was removed with NaOMe in methanol to afford the linker triol 35. Benzoyl chloride was reacted with 35 in pyridine/dichloromethane (1:10) at -78 °C in the presence of DMAP. This method yielded the desired 2'-benzoate 36 (64% yield) in addition to the 2',4'-dibenzoylated product (22%), which upon collection could be converted to the triol 35 by a methanolysis process similar to that of 34 to 35. 2'-Benzoate 36 was trimethoxytritylated at the 4'-position in the presence of Hünig's base in methylene chloride in a yield of over 90%. Rearrangement of 4'-DMT-2'-benzoate 37 to 4'-DMT-3'-benzoate 38 was carried out in n-propanol/pyridine (5:2) in the presence of DMAP, p-nitrophenol and Hünig base. Chromatographic purification afforded 38.Finally, 4'-DMT-3'-benzoate 38 was reacted with ClP(OAl)N(iPr)2 in the presence of Hünig base to prepare phosphoramidite 39 (Scheme 3). This phosphoramidite 39 can be used directly for automated oligonucleotide synthesis without the need to adjust the synthetic scheme.

References