A Mechanistic Study on the Formation of Dronic Acids.

Dronic acid derivatives, important drugs against bone diseases, may be synthesized from the corresponding substituted acetic acid either by reaction with phosphorus trichloride in methanesulfonic acid as the solvent or by using also phosphorous acid as the P-reactant if sulfolane is applied as the medium. The energetics of the two protocols were evaluated by high-level quantum chemical calculations on the formation of fenidronic acid and benzidronic acid. The second option, involving (HO) 2 P-O-PCl 2 as the nucleophile, was found to be more favorable over the first variation, comprising Cl 2 P-O-SO 2 Me as the real reagent, especially for the case of benzidronate.