Cytidine → 2'-O-Methylcytidine

Temperatur

0 °C

Cytidine (100 g, 0.41 mol) was dissolved in warm dimethylformamide (65° C., 1125 mL). The solution was cooled with stirring to 0° C. A slow, steady stream of nitrogen gas was delivered throughout the reaction. Sodium hydride (60% in oil, washed thrice with hexanes, 18 g, 0.45 mol) was added and the mixture was stirred at 0° C. for 45 min. A solution of methyl iodide (92.25 g, 40.5 mL, 0.65 mol) in dimethylformamide (400 mL) was added in portions over 4 h at 0° C. The mixture was stirred for 7 h at 25° C. and then filtered. The filtrate was concentrated to dryness under reduced pressure followed by coevaporation with methanol (2×200 mL). The residue was dissolved in methanol (350 mL). The solution was adsorbed on silica gel (175 g) and evaporated to dryness. The mixture was slurried in dichloromethane (500 mL) and applied on top of a silica gel column (1 kg). The column was eluted with a gradient of dichloromethane-methanol (10:1®2:1). The less polar 2′,3′-dimethyl side product was removed and the coeluting 2′ and 3′-O-methyl product containing fractions were combined and evaporated under reduced pressure to a syrup. The syrup was dissolved in a minimum of hot ethanol (ca. 150 mL) and allowed to cool to 25° C. The resulting precipitate (2′ less soluble) was collected, washed with ethanol (2×25 ml) and dried to give 15.2 g of pure 2′-O-methylcytidine; mp 252–254° C. (lit. mp 252–254° C.); TLC homogenous (Rf 0.50, dichloromethane-methanol 3:1, (Rf of 3′ isomer is 0.50 and the dimethyl product is 0.80). The filtrate was evaporated to give 18 g of a mixture of isomers and sodium iodide.

1. temperatureThe solution was cooled
2. customA slow, steady stream of nitrogen gas was delivered throughout the reaction
3. stirringthe mixture was stirred at 0° C. for 45 min
4. stirringThe mixture was stirred for 7 h at 25° C.
5. filtrationfiltered
6. concentrationThe filtrate was concentrated to dryness under reduced pressure
7. dissolutionThe residue was dissolved in methanol (350 mL)
8. customevaporated to dryness
9. washThe column was eluted with a gradient of dichloromethane-methanol (10:1®2:1)
10. customThe less polar 2′,3′-dimethyl side product was removed
11. additionthe coeluting 2′ and 3′-O-methyl product containing fractions
12. customevaporated under reduced pressure to a syrup
13. dissolutionThe syrup was dissolved in a minimum of hot ethanol (ca. 150 mL)
14. temperatureto cool to 25° C
15. customThe resulting precipitate (2′ less soluble) was collected
16. washwashed with ethanol (2×25 ml)
17. customdried

ORD-Eintrag

ord-98a046380048470dbc82aa170709bfdb

Quelldatensatz

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07138517B2