A Mechanistic Study on the Formation of Dronic Acids.

Péter Ábrányi-Balogh,György Keglevich,István Greiner

doi:10.3390/molecules26247587

Abstract

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)2P-O-PCl2 as the nucleophile, was found to be more favorable over the first variation, comprising Cl2P-O-SO2Me as the real reagent, especially for the case of benzidronate.

Highlights

Hydroxymethylenebisphosphonic acid derivatives include important representatives that are used in the treatment of bone illnesses, such as osteoporosis, the Paget disease, and tumor-induced hypercalcemia [1,2,3,4]
Preparative experiments showed that the reaction of benzoic acid with 3.2 equivalents of PCl3 in methanesulfonic acid (MSA)
The possible mechanistic pathways leading to fenidronic acid and benzidronic acid were computed considering the reaction of benzoic acid or phenylacetic acid and derivatives with PCl3 in MSA or with PCl3 /P(OH)3 in sulfolane

Summary

Introduction

Hydroxymethylenebisphosphonic (dronic) acid derivatives include important representatives that are used in the treatment of bone illnesses, such as osteoporosis, the Paget disease, and tumor-induced hypercalcemia [1,2,3,4]. The general method for the synthesis of dronic acid derivatives involves the reaction of the corresponding substituted acetic acid with phosphorus trichloride (PCl3 ) or with. It was assumed that 1 equivalent of the PCl3 converts the substituted acetic acid to the corresponding chloride, while 2 equivalents are needed to provide the two P-functions Both PCl3 and Cl2 P-O-SO2 Me (formed from PCl3 and MSA) were assumed to be the nucleophiles [10]. At the same time, applying sulfolane as the solvent, there was a need for at least 2 equivalents of both PCl3 and P(OH)3 In this case, Cl2 P-O-P(OH) was found to be the nucleophile [10]. Results of the synthesis of the most important dronic acid derivatives applying the above-mentioned methods (PCl3 /MSA or PCl3 /H3 PO3 /sulfolane) are summarized in. The two models selected were the formation of fenidronate and benzidronate from benzoic acid and phenylacetic acid, respectively, or from their derivatives

A Study on the Formation of Fenidronic Acid

A Study on the Formation of Benzidronic Acid

Conclusions

Computational Protocol