Preparation of mixed trialkyl alkylcarbonate derivatives of etidronic acid via an unusual route

Abstract

SummaryA method to prepare four (3a–d) trialkyl alkylcarbonate esters of etidronate from P,P'-dimethyl etidronate and alkyl chloroformate was developed by utilizing unexpected demethylation and decarboxylation reactions. The reaction with the sterically more hindered isobutyl chloroformate at a lower temperature (90 °C) produced the P,P'-diester (2) as a stable intermediate product. A possible reaction mechanism is discussed to explain these methyl substitutions. These unusual reactions also clarify why it is difficult to prepare alkylcarbonate prodrugs from bisphosphonates. The compounds prepared were analysed by spectroscopic techniques.

Synthesis and Immunomodulatory Activity of Fluorine‐Containing Bisphosphonates

“…[35] Because the cell permeability of BPs is relatively low,p rodrugs of BPs have been designed and synthesized. [36] Esterification of BPs increased their direct cytotoxic activity compared with the corresponding BP acid. [37] This demonstrates the importance of the cell membrane permeability of BPs in determining their biological activity.M oreover, ab i-Scheme2.Procedure for the synthesis of tetrakispivaloxylmethyl-1-fluoro-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonate (11).…”

“…Phosphorus‐containing therapeutics are receiving increasing attention . Because the cell permeability of BPs is relatively low, prodrugs of BPs have been designed and synthesized . Esterification of BPs increased their direct cytotoxic activity compared with the corresponding BP acid .…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…Direct acylation of aminobisphosphonic acids is difficult because this reaction is accompanied by the possible competitive acylation of phosphonic groups [125,126] and hydroxylic groups when amino-1-hydroxy-1,1-bisphosphonic acids are substrates [126,127]. A representative example of this reaction is given in Scheme 28 for alendronic acid 57.…”

“…Classical ones include the formation of Schiff bases, which are then alkylated [150] or reduced [126], and synthesis of thioureido derivatives as intermediates in the preparation of heterocyclic compounds [151][152][153].…”

Synthesis of Triple-Bond-Containing 1-Hydroxy-1,1-bisphosphonic Acid Derivatives To Be Used as Precursors in “Click” Chemistry: Two Examples

“…Our group has extensive experience related to BP synthesis in recent years, − and a while ago we devised three novel applications for BPs: (1) a method for effective removal of chromium(III) from tannery effluents and aqueous solutions based on solid BPs, (2) the first bisphosphonate hydrogelators as potential composers of biocompatible gels, and (3) novel unexpected effects of BPs on plant growth that are nonherbicidal . In addition, we discovered a method for collecting metals from aqueous solutions using an insoluble BP material .…”