Preparation of a fludarabine intermediate via selective alkylation of 2-fluoroadenine.
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.
Schulmeier
Brian E
BE
Genzyme Corporation, Therapeutics Manufacturing and Development, 14805 Omicron Dr., San Antonio, TX 78245, USA.
Cantrell
William R
WR
Bauta
William E
WE
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D000478:Alkylation; D001089:Arabinose / Q000031:analogs & derivatives / Q000737:chemistry; D009690:Nucleic Acid Conformation; D000439:Pentanols / Q000737:chemistry; D013237:Stereoisomerism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
C513441:1,3,5-tri-O-benzyl-1-chloroarabinofuranose; C513440:9-(2,3,5-tri-O-benzylarabinofuranosyl)-2-fluoroadenine; D000439:Pentanols; C038208:2-fluoroadenine; C032765:tert-amyl alcohol; D001089:Arabinose; D014740:Vidarabine; D000225:Adenine; C024352:fludarabine