Optimized synthesis of N-heterocyclic dronic acids; closing a black-box era

To clarify the inconsistent patent literature, the synthesis of Zoledronic and Risedronic acids involving a heterocyclic acetic acid (HAA), phosphorous acid (PA) and phosphorus trichloride (PC) as the reagents, and methanesulfonic acid as the solvent was studied in detail. It was found that the best synthesis can be accomplished at 80 degrees C using HAA and PC in a 1:3.1 molar ratio without any PA. (C) 2011 Elsevier Ltd. All rights reserved.