Syntheses of phosphonic esters of alendronate, pamidronate and neridronate

Several synthetic pathways for obtaining phosphonic esters of the amino bisphosphonic acids (NBPs) pamidronate, alendronate and neridronate were investigated. The general guideline was to react N-protected amino acids activated as phthalimide esters or as acyl chlorides. Succinimide esters were found less reactive and quickly abandoned. gamma-Lactam formation arises when starting from Boc- or Cbz-protected amino acids. The phthalimide N-protecting group allowed access to alkyl or aryl mono-, di- (symmetric or not) and tri-esters of these three NBPs in high yields. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).