146-78-1

75607-67-9

The general procedure for the synthesis of ((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methylphosphonic acid dihydrogen ester from 2-fluoroadenosine is as follows: Example 1: Fludarabine (19.5 g, 0.0683 mol) and triethylphosphate (79.1 ml, 0.465 mol) were added to a reactor pre-cooled to -15/-20°C. Trichlorophosphate (15.3 ml, 0.164 mole) was added slowly and dropwise over a period of about 1 hour while the reaction temperature was controlled to be maintained at -10/-15°C. The reaction mixture was stirred continuously for 48 hours until HPLC analysis showed that the amount of fludarabine was less than 2%. Subsequently, pre-cooled toluene (780 ml, 40 v/v) was slowly added over a period of about 1.5 hours and stirring was continued for 1-2 hours at -10/-15°C. The reaction was completed by filtration and the filter cake was washed with toluene (20 ml). The wetted solid (ca. 35 g) was suspended in water (40 ml) and the pH was adjusted to 11 with 32% sodium hydroxide solution (ca. 20 ml). the resulting solution was transferred to Dowex resin that had been pretreated (activation and washing: washed sequentially with softened water to colorless, acidified with 5% hydrochloric acid (ca. 200 ml), and washed with softened water to a neutral pH). Filtration is carried out after stirring for 15 minutes. The resin was again suspended in water (500 ml), stirred for 15 minutes and filtered. This was repeated until no fludarabine phosphate was detected in the filtrate. The product-containing filtrates were combined and concentrated under reduced pressure at 30-35°C until the product began to precipitate, filtered and dried under vacuum at 60°C to constant weight to give 10 g of white solid (40% yield) with >97.5% purity. Recrystallization step: the above solid was suspended in 10 volumes of water, heated at 70°C for 1 hour, hot filtered, and the filter cake was washed with acetone to obtain a white solid with purity >99%.