Heteroarylacetyl chlorides and mixed anhydrides as intermediates in the synthesis of heterocyclic dronic acids

György Keglevich, Alajos Grün, Rita Kovács, Katalin Koós, Beáta Szolnoki, Sándor Garadnay, József Neu, László Drahos, István Greiner

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It has been recognised that there is no need for phosphorous acid during the conversion of 1-heteroarylacetic acids to the corresponding dronic acids, as phosphorus trichloride (PCl 3) is the real reagent. We could prove that the first intermediate toward the formation Risedronic acid is 3-pyridylacetyl chloride that was prepared in different ways using inorganic halides in toluene or in methanesulfonic acid (MSA). The intermediate was then reacted with two equivalents of PCl 3 to afford risedronic acid after hydrolysis and pH adjustment. The pyridylacetyl chloride intermediate was identified on the basis of its esterification and amidation reaction. In MSA as the solvent, mixed anhydrides may also be formed as the intermediates from which the dronic acids may be formed in reaction with PCl 3. A similar situation was anticipated for the reaction sequence of Zoledronic acid.

Original languageEnglish
Pages (from-to)345-351
Number of pages7
JournalLetters in Drug Design and Discovery
Issue number4
Publication statusPublished - May 1 2012



  • Alkyl heteroarylacetate
  • Dronic acids
  • Heteroarylacetamide
  • Heteroarylacetic acid
  • Heteroarylacetyl chloride
  • Phosphorus trichloride

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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