Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters

Abstract

Selective methods for the synthesis of (1-hydroxyeth- ylidene)-1,1-bisphosphonate tri-, P,P -di-, P,P-di- and mono esters have been developed. Preparation is started from selected symmet- ric or unsymmetric tetraesters of etidronate using alkalimetal salts or trimethylsilyl iodide as dealkylating agents. Synthesis of H3CC(OH)(P(O)(OH)2)(P(O)(OH)(OHex)) starting from trimethyl ester of etidronate is also described. 1 H, 13 C and 31 P NMR data are reported including 1 JCP, 2 JCP and 2 JPP couplings. The solid state structure is given for (1-(dimethoxyphosphinyl)-1-hydroxyethyl)- 1-phosphonic acid monomethyl ester monopotassium salt (1a).