N,N-Dimethylaniline → (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate

HRID 966383Notes

Reaction equation

HRID 966383 reaction equation
[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=O)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:55])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:27][C:26]1[N:28]=[C:29]2[C:22]([N:21]=[CH:20][N:19]2[C@@H:6]2[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:23]([Cl:55])[N:25]=1

Participants

7

Reactant 4

HCID 949N,N-DimethylanilineHCID 14812Phosphorus oxide (P4O10)HCID 24813Phosphorus oxychlorideHCID 135465084Tri-O-acetylguanosine

Product 1

HCID 10788628(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate

Reagents, catalysts & solvents 2

HCID 5946Tetraethylammonium ChlorideCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
47.5 °C

Procedure

An 8-liter, 3-neck, round bottom flask equipped with a mechanical stirrer, a condenser, a thermometer, and an argon inlet is charged with dry acetonitrile (2.2 liters) and 2′,3′,5′-tri-O-acetyl-guanosine (550 g, 1.344 moles). Tetraethylammonium chloride (423 g, 2.55 moles), previously dried for 18 hours over P2O5 at 110° C./high vacuum is added to afford a clear, green solution. After heating to 45-50° C., N,N-dimethylaniline (179 g, 1.48 moles) is added, followed by phosphorus oxychloride (825 g, 5.38 moles) over 15 minutes, during which the temperature rose to 75±3° C. The mixture was kept at 75±3° C. for 15 minutes, flash evaporated (TBath<40° C.), and the dark red residue taken up in dichloromethane (4 liters). With vigorous stirring, the mixture is washed with ice water (2.5 L), the organic phase is collected, and the aqueous phase extracted with additional dichloromethane (2×1 L). The combined organic phases are washed with cold water (2×2 liters), saturated aqueous NaHCO3 (2×2 L), dried (Na2SO4), filtered, and concentrated to approximately 1.5 liters. Absolute ethanol (1.5 L) is added and the mixture concentrated to approximately 2 liters. Upon cooling to room temperature, the product crystallizes as a colorless solid (321 g, 56%) after drying in vacuo at 40° C. for 17 hours.

Workup

  1. customAn 8-liter, 3-neck, round bottom flask equipped with a mechanical stirrer, a condenser
  2. additionis added
  3. customto afford a clear, green solution
  4. customrose to 75±3° C
  5. customflash evaporated (TBath<40° C.)
  6. washWith vigorous stirring, the mixture is washed with ice water (2.5 L)
  7. customthe organic phase is collected
  8. extractionthe aqueous phase extracted with additional dichloromethane (2×1 L)
  9. washThe combined organic phases are washed with cold water (2×2 liters), saturated aqueous NaHCO3 (2×2 L)
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated to approximately 1.5 liters
  13. additionAbsolute ethanol (1.5 L) is added
  14. concentrationthe mixture concentrated to approximately 2 liters
  15. temperatureUpon cooling to room temperature
  16. customthe product crystallizes as a colorless solid (321 g, 56%)
  17. customafter drying in vacuo at 40° C. for 17 hours

Sources & evidence

ORD record
ord-73b05cb97e094fd58f1678b24cf21898
Source dataset
uspto-grants-2005_10
Patent number
US06951932B2

Reaction notes

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