Reaktion #1447119

Reaktionsgleichung

2′-C-Methylcytidine

tert-butylmagnesium chloride

propylpentyl N-[chloro(phenyloxy)phosphoryl]-L-alaninate

→

title compounds

5′-O-[[[(1S)-1-methyl-2-oxo-2-[(propylpentyl)oxy]ethyl]amino]phenoxyphosphinyl]-2′-C-methylcytidine

Lösungsmittel

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe mixture was immediately warmed to 0° C.
2. 2
   Temperaturagain cooled to −78° C.
3. 3
   workup.WAITto reach RT overnight
4. 4
   Sonstigewas quenched by the addition of water
5. 5
   ExtraktionThe aqueous phase was extracted three times with EtOAc
6. 6
   Trocknenthe combined organic phases were dried over Na2SO4
7. 7
   SonstigeThe crude product was purified by column chromatography on silica gel (DCM/MeOH 92:8)
8. 8
   workup.DISSOLUTIONthe resulting off white solid was dissolved in DMSO
9. 9
   Sonstigepurified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O, water buffered with 5 mM AMBIC)
10. 10
    workup.ADDITIONFractions containing the pure diastereoisomers
11. 11
    Sonstigefreeze-dried

Vorschrift

2′-C-Methylcytidine was diluted with THF (0.097 M). The resulting slurry was cooled to −78° C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0° C., stirred for 30 min and again cooled to −78° C., then propylpentyl N-[chloro(phenyloxy)phosphoryl]-L-alaninate (as 1.0 M solution in THF, 2.2 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried over Na2SO4. The crude product was purified by column chromatography on silica gel (DCM/MeOH 92:8), and the resulting off white solid was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O, water buffered with 5 mM AMBIC). Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as a white solid.

Quelle