Bromotrimethylsilane → Adefovir

HRID 133115

Reaktionsgleichung

Reaktionsgleichung von HRID 133115
[OH:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].CC(C)[O-].[Mg+2].CC(C)[O-].CC(C)([O-])C.[Mg+2].CC(C)([O-])C.C1(C)C=CC(S(O[CH2:44][P:45](=[O:52])([O:49]CC)[O:46]CC)(=O)=O)=CC=1.Br[Si](C)(C)C>CN(C=O)C.O>[P:45]([CH2:44][O:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13])([OH:52])([OH:49])=[O:46]

Komponenten

8

Edukt 5

HCID 76113BromotrimethylsilaneHCID 2426522-(6-Aminopurin-9-yl)ethanolHCID 4193599Diethyl P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]phosphonateHCID 10197750Magnesium dipropan-2-olateHCID 12040442Magnesium 2-methylpropan-2-olate

Produkt 1

HCID 60172AdefovirAusbeute 65,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

9-(2-Hydroxyethyl)adenine (HEA) (20.0 g, 0.112 mol) was suspended in DMF (125 ml) and heated to 80° C. Magnesium isopropoxide (11.2 g, 0.0784 mol), or alternatively magnesium t-butoxide, was added to the mixture followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.162 mol) over one hour. The mixture was stirred at 80° C. for 7 hours. 30 ml of volatiles were removed via vacuum distillation and the reaction was recharged with 30 ml of fresh DMF. After cooling to room temperature, bromotrimethylsilane (69.6 g, 0.450 mol) was added and the mixture heated to 80° C. for 6 hours. The reaction was concentrated to yield a thick gum. The gum was dissolved into 360 ml water, extracted with 120 ml dichloromethane, adjusted to pH 3.2 with sodium hydroxide, and the resulting slurry stirred at room temperature overnight. The slurry was cooled to 4° C. for one hour. The solids were isolated by filtration, washed with water (2×), and dried in vacuo at 56° C. to yield 20 g (65.4%) of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as a white solid. Mp:>200° C. dec. 1H NMR (D2O) δ 3.49 (t, 2H); 3.94 (t, 2H); 4.39 (t, 2H); 8.13 (s, 1H); 8.22 (s, 1H).

Aufarbeitung

  1. custom30 ml of volatiles were removed via vacuum distillation
  2. temperatureAfter cooling to room temperature
  3. temperaturethe mixture heated to 80° C. for 6 hours
  4. concentrationThe reaction was concentrated
  5. customto yield a thick gum
  6. extractionextracted with 120 ml dichloromethane
  7. stirringthe resulting slurry stirred at room temperature overnight
  8. temperatureThe slurry was cooled to 4° C. for one hour
  9. customThe solids were isolated by filtration
  10. washwashed with water (2×)
  11. customdried in vacuo at 56° C.

Quellen und Nachweise

ORD-Eintrag
ord-8cd7c6c8eaed4eedadde19e8a7176674
Quelldatensatz
uspto-grants-2008_06
Patentnummer
US07390791B2

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