Reacción #1447119

Ecuación de reacción

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

Disolventes

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe mixture was immediately warmed to 0° C.
2. 2
   Temperaturaagain cooled to −78° C.
3. 3
   workup.WAITto reach RT overnight
4. 4
   Otrowas quenched by the addition of water
5. 5
   ExtracciónThe aqueous phase was extracted three times with EtOAc
6. 6
   Secadothe combined organic phases were dried over Na2SO4
7. 7
   OtroThe 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
   Otropurified 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
    Otrofreeze-dried

Procedimiento

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.

Fuente