Sodium hydride → HCID 16110080, Verbindung

Temperatur

-20 °C

A solution of 1-[(2S)-2-hydroxy-3-(triphenylmethoxy)propyl]-5-azacytosine (934 mg, 2.18 mmol) and diisopropyl tosyloxymethylphosphonate (1.05 g, 3 mmol) in DMF (30 ml) was cooled to −20° C. and 60% oil dispersion of NaH (240 mg, 6 mmol) was added. The mixture was stirred at −20° C. for 15 min, then the temperature was let to rise to approx. 25° C. (room temperature) and the stirring continued for additional 15 h. Acetic acid was added drop wise to pH 7, the mixture evaporated and the residue coevaporated with toluene (2×50 ml). Acetonitrile (30 ml) was added, followed by bromotrimethylsilane (2.7 ml, 20 mmol), the resulting suspension stirred in dark at room temperature for 48 h and evaporated. The residue was coevaporated with acetonitrile (3×50 ml). 90% Aqueous solution of methanol (50 ml) was added and the solution neutralized to pH 7.0 with 0.2 M triethylammonium hydrogencarbonate. The solution was concentrated to minimal volume (approx. 5 ml) and partitioned between water (100 ml) and ether (100 ml). An aqueous layer was concentrated to a volume 5 ml and applied onto a column of Dowex 1 (AcO− form, 60 ml). Elution was performed with water (300 ml), then with a linear gradient of acetic acid (0.5-1 M, 1 l) and lastly, the pure product was eluted with 1 M formic acid. UV absorbing fractions were taken down in vacuo and the residue coevaporated several times with water till a complete removal of acid. The residue was crystallized from aqueous ethanol, crystals collected by suction, washed with ethanol and ether and dried in vacuo. Yield: 200 mg (33%) of pure HPMP-5-azaC.

1. customto rise to approx. 25° C.
2. custom(room temperature)
3. waitthe stirring continued for additional 15 h
4. customthe mixture evaporated
5. additionAcetonitrile (30 ml) was added
6. stirringthe resulting suspension stirred in dark at room temperature for 48 h
7. customevaporated
8. addition90% Aqueous solution of methanol (50 ml) was added
9. concentrationThe solution was concentrated to minimal volume (approx. 5 ml)
10. custompartitioned between water (100 ml) and ether (100 ml)
11. concentrationAn aqueous layer was concentrated to a volume 5 ml
12. washElution
13. washwith a linear gradient of acetic acid (0.5-1 M, 1 l) and lastly, the pure product was eluted with 1 M formic acid
14. customUV absorbing fractions
15. customtill a complete removal of acid
16. customThe residue was crystallized from aqueous ethanol, crystals
17. customcollected by suction
18. washwashed with ethanol and ether
19. customdried in vacuo

ORD-Eintrag

ord-10c4fd24000d41638455a2bf6db34f20

Quelldatensatz

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08153787B2