Preparation of a fludarabine intermediate via selective alkylation of 2-fluoroadenine
Brian E Schulmeier1, William R Cantrell, William E Bauta
1Genzyme Corporation, Therapeutics Manufacturing and Development, 14805 Omicron Dr., San Antonio, TX 78245, USA.
Abstract:
The reaction between 2-fluoroadenine (3) and 1,3,5-tri-O-benzyl-1-alpha-D-chloroarabinofuranose (4) with potassium t-amylate was evaluated in various solvents to afford 9-beta-D-(2,3,5-tri-O-benzyl-arabinofuranosyl)-2-fluoroadenine (5) and the corresponding alpha-anomer (6). In addition, 7-beta-D-(2,3,5-tri-O-benzyl-arabinofuranosyl)-2-fluoroadenine (7) and an unusual "bis-fluoroadenine" nucleoside (8) were isolated as byproducts. The highest anomeric ratio (beta/alpha > 10) and conversion (> 80%) were observed with the highly polar solvent sulfolane. This reaction was demonstrated on gram scale as a practical laboratory synthesis of 5, a known intermediate in the synthesis of fludarabine.
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