Water → HCID 178476325, compound

HRID 357491Notes

Reaction equation

HRID 357491 reaction equation
[CH:1]1[N:5]([CH2:6][O:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[C:4]2[N:13]=[C:14]([NH2:18])[N:15]=[C:16]([OH:17])[C:3]=2[N:2]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S([O-])(=O)=O)=[CH:21][CH:20]=1.[NH+]1C=C[CH:33]=[CH:32][CH:31]=1.[OH2:36].[C:37]([O:40]C(C)C)(=[O:39])[CH3:38]>C(OC)(OC)(OC)C.CN(C)C=O>[CH3:31][CH:32]([C@H:38]([NH:15][C:16]([O:17][CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:36])[C:37]([OH:40])=[O:39])[CH3:33].[CH3:38][C:37]([O:10][CH2:9][CH:8]([O:7][CH2:6][N:5]1[C:4]2[NH:13][C:14]([NH2:18])=[N:15][C:16](=[O:17])[C:3]=2[N:2]=[CH:1]1)[CH2:11][OH:12])=[O:39]

Participants

7

Reactant 4

HCID 962WaterHCID 7915Isopropyl AcetateHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 178418321HCID 178418321, compound

Product 1

HCID 178476325HCID 178476325, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 15050Trimethyl orthoacetateSolvent

Procedure

To a slurry of 5 g of ganciclovir in 10 ml of trimethyl orthoacetate and 10 ml of dimethylformamide was added 0.2 g of pyridinium p-toluene-sulfonate (PPTS). The slurry was stirred at room temperature overnight. Then 5 ml of tap water was added to the thick white slurry and stirring was continued for 1.5 hours. 150 ml of isopropyl acetate was added to the reaction mixture. The mixture was then vacuum distilled at approximately 100-150 mm of Hg (torr) until the volume was about 20 ml. To the concentrate was then added 7.0 g of Z-valine-NCA and 0.2 g of 4-dimethylaminopyridine (DMAP). The mixture was stirred until all the solid had dissolved. The reaction was followed by HPLC. An additional 0.5 g of Z-valine-NCA was needed to complete the process. Then 150 ml of isopropyl acetate was added and the mixture was heated to 50°-55° C. for 30 min. The mixture was allowed to cool slowly and stirred overnight with very slow agitation. The slurry was filtered and washed twice with 10 ml each of isopropyl acetate. The white solid was dried in a vacuum oven at ca. 500 mm of Hg (torr), (nitrogen sweep, 600) to give 7.82 g of Z-valine-ganciclovir monoacetate. HPLC analysis: 94% Z-valine-ganciclovir monoacetate, 0.8% bis-Z-valinate. 1H-NMR (diastereomeric mixture): δ 0.8 (two d,6H), 1.8 (two s,3H), 1.9 (m,1H), 3.95 (m,6H), 5.0 (s,2H), 5.4 (s,2H), 6.5 (s,2H), 7.3 (m,5H), 7.7 (two d,1H), 7.8 (s,1H), 10.6 (s,1H).

Workup

  1. stirringstirring
  2. waitwas continued for 1.5 hours
  3. distillationvacuum distilled at approximately 100-150 mm of Hg (torr) until the volume
  4. additionTo the concentrate was then added 7.0 g of Z-valine-NCA and 0.2 g of 4-dimethylaminopyridine (DMAP)
  5. stirringThe mixture was stirred until all the solid
  6. dissolutionhad dissolved
  7. additionThen 150 ml of isopropyl acetate was added
  8. temperaturethe mixture was heated to 50°-55° C. for 30 min
  9. temperatureto cool slowly
  10. stirringstirred overnight with very slow agitation
  11. filtrationThe slurry was filtered
  12. washwashed twice with 10 ml each of isopropyl acetate
  13. customThe white solid was dried in a vacuum oven at ca. 500 mm of Hg (torr), (nitrogen sweep, 600)

Sources & evidence

ORD record
ord-9de1c6568c91475da4e78bedf95d8875
Source dataset
uspto-grants-1998_11
Patent number
US05840890

Reaction notes

Loading…