SYNTHESIS OF α-HALOGENATED METHANEDIPHOSPHONATES^{1a, b}

Abstract

Methanediphospnonate (MDP) anions can exhibit anti-viral activity, inhibit bone resorption, and act as ligands in radiopharmaceuticals. α-Halo-substitution provides MDP derivatives (XYMDP, where × = H, F, CI or Br; Y = F, Cl or Br) with modified acid-base, steric and other properties. These compounds are conveniently made from the corresponding α-halogenated XYMDP esters (RO)₂P(O)CXYP(O)(OR)₂. Detailed procedures are given for synthesis of R₄ XYMDP for R = Prⁱ and X, Y = H. Cl; Cl, Cl; H, Br; Br, Br; F, Cl; F, Br and Cl, Br in 88–96% yield; for R = Et and X, Y = H, Cl; Cl. Cl; H, Br; Br, Br and Cl, F in 81–94% yield; and for R = Me and X, Y = Cl, Cl and Br, Br in 72–80% yield. NMR data (¹H, ³¹P, ¹³C. (¹⁹F)) are presented for the products obtained. The XYMDP acids (X, Y = H, Cl; Cl, Cl; H, Br; Br, Br; F, Cl; F, Br and Cl, Br) were prepared by HCl hydrolysis of a corresponding ester and characterized as tris(dicyclohexylammonium) salts by elemental analyses and ³¹P NMR.