Ethyl Acetate → (2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate

HRID 1700104Notes

Reaction equation

HRID 1700104 reaction equation
[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34](OC(=O)C)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(OCC)(=O)C>ClC(Cl)(Cl)C>[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28]

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 65367Trimethylsilyl triflateHCID 830641,2,3,5-Tetraacetyl-beta-D-ribofuranoseHCID 178419062HCID 178419062, compound

Product 1

HCID 58904389(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetateYield 47.3%

Reagents, catalysts & solvents 1

HCID 62781,1,1-TrichloroethaneSolvent

Procedure

N,O-Bistrimethylsilylacetamide (44 ml, 0.18 mol) was added to a suspension of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (10.0 g, 0.03 mol) (see WO-A-00/23457) in 1,1,1-trichloroethane (250 ml). The suspension was heated to reflux. When all suspended solid had dissolved the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was twice dissolved in toluene (50 ml) and the solvent removed under reduced pressure. The residue was then dissolved in toluene (100 ml) and (2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate (10.3 g, 0.032 mol) was added. The solution was stirred at room temperature and trimethylsilyltrifluoromethanesulphonate (16 ml, 0.088 mol) was carefully added. The resulting solution was heated under reflux for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted by the addition of ethyl acetate (100 ml) and then washed with saturated aqueous sodium hydrogen carbonate (ten portions of 100 ml) and saturated aqueous sodium chloride solution (100 ml). The aqueous extracts were combined and washed with ethyl acetate (three portions of 100 ml). The combined organic layers were dried (anhydrous magnesium sulphate) and the solvent was removed under reduced pressure to give a solid that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 by volume gradually changing to 80:20:3 by volume) to give the title compound as a foam (8.5 g).

Workup

  1. temperatureThe suspension was heated to reflux
  2. dissolutionWhen all suspended solid had dissolved the reaction mixture
  3. customthe solvent was removed under reduced pressure
  4. dissolutionThe residue was twice dissolved in toluene (50 ml)
  5. customthe solvent removed under reduced pressure
  6. dissolutionThe residue was then dissolved in toluene (100 ml)
  7. temperatureThe resulting solution was heated
  8. temperatureunder reflux for 2 hours
  9. temperatureto cool to room temperature
  10. washwashed with saturated aqueous sodium hydrogen carbonate (ten portions of 100 ml) and saturated aqueous sodium chloride solution (100 ml)
  11. washwashed with ethyl acetate (three portions of 100 ml)
  12. dry with materialThe combined organic layers were dried (anhydrous magnesium sulphate)
  13. customthe solvent was removed under reduced pressure
  14. customto give a solid
  15. customthat was purified by column chromatography on silica gel eluting with dichloromethane

Sources & evidence

ORD record
ord-85187da75e5f4100bd00b25b0186ff4f
Source dataset
uspto-grants-2002_02
Patent number
US06350735B1

Reaction notes

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