Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives in Different Solvents

Abstract

Abstract:The syntheses of hydroxymethylenebisphosphonic acid derivatives (dronic acid derivatives) starting from the corresponding substituted acetic acids and P-reagents, mainly phosphorus trichloride and phosphorous acid are surveyed according to the solvents applied. The nature of the solvent is a critical point due to the heterogeneity of the reaction mixtures. This review sheds light on the optimum choice and ratio of the P-reactants, and on the optimum conditions.

Biszfoszfonátok előállításának vizsgálata

“…Hidrolízist és szükség szerinti pH állítást, majd tisztítást követõen kapják meg a kívánt terméket (7. ábra). 2,11,12 7. Ábra.…”

“…A P-reagensek szerepe, a reakciómechanizmus, az optimális körülmények sem tisztázottak az irodalomban, ráadásul többször egymásnak ellentmondóak, a reakció egyfajta "fekete doboznak" volt tekinthetõ egészen a közelmúltig. 2,11,12 …”

“…The role of the P-reactants and the solvents have not been investigated, and the mechanism has not been explored. 2,11,12 The research was started by the investigation of the preparation of zoledronate (11) and risedronate (12) in methanesulfonic acid (MSA). The corresponding carboxylic acid was reacted with phosphorus trichloride and phosphorous acid in different ratios (Scheme 8).…”

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

“…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 nitriles/acid chlorides/anhydrides, giving C -substituted methylenediphosphonic acid tetraesters with amino or hydroxyl group at the carbon of the > P-C-P < backbone [ 10 , 17 , 18 , 19 ]. The second group of methods proceeds from methylenediphosphonic acid tetraesters and consists in functionalization of the methylene group that is a CH-acid.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…The reaction is carried out in selected solvents (phenylsulphonic acid, various phenols, chlorobenzene, diphenyl ether or ionic liquids) with sulfone and methanesulphonic acid being preferred choices [11,[15][16][17][18][19][20]. Despite many theories [19,[21][22][23], the exact mechanism of this reaction is not fully understood; however, the formation of acid chloride as a first intermediate has been undoubtedly demonstrated (Scheme 1). This intermediate may react with methanesulphonic acid (when used as a solvent), and the formed mixed anhydride is also considered a potential intermediate for the next step [24], which is an Arbuzov-like reaction of phosphorus acid or one of its several derivatives (including anhydrides of variable structure [17]) formed during the reaction.…”