The general procedure for the synthesis of 2-((2-amino-6-oxo-1H-purin-9(6H)-yl)methoxy)-3-hydroxypropyl acetate from 1-acetylimidazole and 2-amino-9-(((1,3-dihydroxypropan-2- yl)oxy)methyl)-1H-purin-6(9H)-one is as follows: 500.0 g (1.96 mol, 1.0 equiv) of ganciclovir, 244.4 g (2.35 mol, 1.2 eq.) of trimethyl borate and 7.5 kg of toluene were added to the reaction vessel and heated to reflux for 5 hours. The progress of the reaction was monitored by TLC to confirm the complete reaction of the ingredients. The reaction mixture was cooled to room temperature and 396.7 g (3.93 mol, 2.0 eq.) of triethylamine was added, followed by 323.7 g (2.94 mol, 1.5 eq.) of 1-acetylimidazole, and stirred for 6 hours at room temperature. The ratio of monoacetyl ganciclovir to N,O-diacetyl ganciclovir was analyzed by HPLC to be 94:4. The reaction mixture was cooled to 0-10 °C and 2.0 kg of methanol was slowly added dropwise followed by stirring for 2 h at room temperature. The solvent was removed by concentration under reduced pressure, 3.0 kg of ethyl acetate was added, the organic layer was washed with 500 g of water and the aqueous layer was extracted with 500 g of ethyl acetate. The organic layers were combined, concentrated under reduced pressure and recrystallized by ethanol to give 440.9 g of colorless crystal product in 75.7% yield and 99.2% purity.
