Practical and reliable synthesis of 1,3,4,6-tetra--acetyl-2-- trifluoromethanesulfonyl-?-D-mannopyranose, a Precursor of 2-Deoxy-2-[F]fluoro-D-glucose (FDG)

To develop a practical and reliable synthesis of 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-beta-D-mannopyranose (mannose triflate), a precursor of 2-deoxy-2-[18F]fluoro-D-glucose (FDG).The key intermediate in the preparation of the triflate precursor, 1,3,4,6-tetra-O-acetyl-beta-D-mannopyranose, was synthesized starting from D-mannose via the following four steps: (1) per-O-acetylation with Ac2O-I2, (2) formation of acetobromomannose with 30% HBr in AcOH, (3) 1,2-orthoester formation with EtOH-2,4,6-collidine and (4) hydrolysis of the 1,2-orthoester with 1M aqueous HCl. Triflation of this key intermediate with Tf2O-pyridine then completed the synthesis of the mannose triflate.Starting from 200 g of D-mannose, the triflate precursor was synthesized with an overall yield of 65 g to 85 g (12% to 16%) in approximately seven days. The inherent low efficiency of the orthoester hydrolysis was compensated by the quantitative recovery and subsequent recycling of penta-O-acetyl-D-mannopyranose.A large-scale preparation of mannose triflate is now routinely carried out to satisfy the growing needs for FDG in both research centers and hospitals.