反应详情

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, 60°) 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).

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, 60°)