A facile one pot synthesis of bisphosphonic acids and their sodium salts from nitriles

Abstract

A general and one pot synthesis for the preparation of bisphosphonic acids and their sodium salts (2a-e) from nitriles (3a-e) is described. This method involves hydrolysis of nitriles (3a-e) to the corresponding acids and subsequent bisphosphonation in a single solvent to produce bisphonates (2a-e). Preparations of some of bisphosphonates, which are presently in clinical use like risedronate (2a) sodium, ibandronate sodium (2d) are synthesized by following this new method. This method is useful for the preparation of other bisphosphonate compounds.

Surface Modification Using Phosphonic Acids and Esters

“…143 Finally, in situ generation of the carboxylic acid by hydrolysis of the corresponding nitrile in aqueous methanesulfonic acid, and subsequent treatment with phosphorus trichloride was also found to be a powerful method to prepare various hydroxylbisphosphonic acids in good yields. 144 Moreover, the introduction of gem-bisphosphonate moieties has also been reported by Kaboudin et al 145 by treatment of primary amines with triethyl orthoformate and diethyl phosphite under microwave irradiation (Scheme 17), reaction known as the Kabachnik−Fields reaction. The same endproducts were also obtained upon treatment of primary amines with tetraethyl diphosphonodiazomethane [Et 2 O 3 P−(C N 2 )−PO 3 Et 2 ] in the presence of rhodium catalysts, 146 while this reaction works similarly with alcohols.…”

“…Finally, in situ generation of the carboxylic acid by hydrolysis of the corresponding nitrile in aqueous methanesulfonic acid, and subsequent treatment with phosphorus trichloride was also found to be a powerful method to prepare various hydroxyl-bisphosphonic acids in good yields …”

ZnCl2-Mediated Double Addition of Dialkylphosphite to Nitriles for the Synthesis of 1-Aminobisphosphonates

“…ABPs are prepared by several methods including: a prolonged heating of a mixture of nitriles with phosphorus trichloride in the presence of excess phosphoric acid, the acid-catalyzed Beckmann rearrangement of oximes in the presence of phosphites, the condensation reaction of amines with phosphites in the presence of ethylorthoformate, the phosphonylation of nitriles in the presence of SnCl 2 /HCl or by double radical transfer mediated by titanocene/propylene oxide, and the rhodium-catalyzed N–H insertion reaction of amines with diphosphonodiazomethane carbene . Recently, Wang and Huang reported the bisphosphorylation of amides in the presence of Tf 2 O for the preparation of 1-amino bisphosphonates .…”