Heteroarylacetyl Chlorides and Mixed Anhydrides as Intermediates in the Synthesis of Heterocyclic Dronic Acids

Gyorgy Keglevich, Alajos Grun, Rita Kovacs, Katalin Koos, Beata Szolnoki, Sandor Garadnay, Jozsef Neu, Laszlo Drahos; Istvan Greiner

Abstract

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 (PCl3) 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 PCl3 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 PCl3. A similar situation was anticipated for the reaction sequence of Zoledronic acid.

Keywords: Heteroarylacetic acid, Phosphorus trichloride, Heteroarylacetyl chloride, Alkyl heteroarylacetate, Heteroarylacetamide, Dronic acids, phosphorous acid, methanesulfonic acid (MSA), dronates, osteoporosis, Geminal bisphosphonates, hydroxy group, Alkyl Heteroarylacetates, pyridylacetyl chloride, Risedronic Acid, alkyl esters