On the Reaction of Carbonyl Diphosphonic Acid with Hydroxylamine and O-alkylhydroxylamines: Unexpected Degradation of P-C-P Bridge.

Olga Khomich,Dmitry Yanvarev,Alexey Kornev,Roman Novikov,Sergey Kochetkov,Alex Khomutov,Jouko Vepsäläinen,Elina Puljulla

doi:10.3390/molecules22071040

Abstract

Derivatives of methylenediphosphonic acid possess wide spectra of biological activities and are used in enzymology as research tools as well as in practical medicine. Carbonyl diphosphonic acid is a promising starting building block for synthesis of functionally substituted methylenediphosphonates. Investigation of the interaction of carbonyl diphosphonic acid with hydroxylamine clearly demonstrates that it is impossible to isolate oxime within the pH range 2–12, while only cyanophosphonic and phosphoric acids are the products of the fast proceeding Beckmann-like fragmentation. In the case of O-alkylhydroxylamines, corresponding alcohols are found in the reaction mixtures in addition to cyanophosphonic and phosphoric acids. Therefore, two residues of phosphonic acid being attached to a carbonyl group provide new properties to this carbonyl group, making its oximes very unstable. This principally differs carbonyl diphosphonic acid from structurally related phosphonoglyoxalic acid and other α-ketophosphonates.

Highlights

Non-hydrolyzable analogues of inorganic pyrophosphate, i.e., derivatives of methylenediphosphonic acid, are used in biochemistry as a source of the inhibitors of the pyrophosphate- related enzymes and for the investigation of their reaction mechanisms
Methods of synthesis of functionally substituted methylene bisphosphonates can be divided into two main groups
ItItisisknown exists in equilibrium equilibrium with with knownthat thatcarbonyl carbonyldiphosphonic diphosphonic acid acid 11 in in aqueous aqueous solutions solutions exists

Summary

Introduction

Non-hydrolyzable analogues of inorganic pyrophosphate, i.e., derivatives of methylenediphosphonic acid, are used in biochemistry as a source of the inhibitors of the pyrophosphate- related enzymes and for the investigation of their reaction mechanisms (for review see [1,2,3]). Complexes of medronic and etidronic acids, and their derivatives with 99m Tc, are used in radiometal-based imaging of bone diseases [5]; while, for example, 11-amino-1-hydroxyundecylidene-1,1-bisphosphonic acid (Figure 1) has high practical potential as an effective chelator of heavy metals ions and rare-earth elements [6]. By varying the structure of the substituents at the carbon atom of methylenediphosphonic acid and to change change the the spectrum spectrumof ofbiological biological acid andthe thestructure structureof ofchelating chelating group, group, itit appeared appeared possible possible to activity of bisphosphonates. Methods of synthesis of functionally substituted methylene bisphosphonates can be divided into two main groups. The first one is comprised of the reaction of phosphorous acids derivatives with two main groups. C-substituted methylenediphosphonic from tetraesters by acidic hydrolysis [20], or using trimethylbromosilane [21].

Results and Discussion

Eand Z-isomers

Materials and Methods