The Synthesis of Pamidronic Derivatives in Different Solvents: An Optimization and a Mechanistic Study

Abstract

The synthesis of pamidronic acid and sodium pamidronate dihydrate from β‐alanine and P‐reagents (phosphorus trichloride and phosphorous acid) was investigated at 75°C in different solvents, and the preparation was optimized. In sulfolane, the use of 2 equiv of phosphorus trichloride and phosphorous acid was found the optimum to lead to pamidronic acid in a yield of 63%. In methanesulfonic acid, 3.2 equiv of phosphorus trichloride was necessary without any phosphorous acid to give pamidronate dihydrate in the best yield (57%) after hydrolysis and pH adjustment. In the first case, the P‐nucleophile may be (HO)2P–O–PCl–O–P(OH)2 or (HO)2P–O–PCl2, whereas in the second case, the P‐reactant is probable Cl2P–O–S(O)2Me. It can be said that the mechanism proposed for the formation of pamidronic acid is highly influenced by the solvent used, as it determines the necessary P‐reagent(s). Our results promote the “on purpose” planning of the synthesis of dronates.

Biszfoszfonátok előállításának vizsgálata

“…13 Our method was extended for the preparation of pamidronate (18), alendronate (19), ibandronate (20), etidronate (21) and fenidronate (22) (Scheme 10). [14][15][16][17] Based on our experiments, a mechanism was proposed. According to this, anhydride type intermediate Cl 2 P-O-SO 2 Me (23) was assumed as an activated P-reagents.…”

“…Ábra. Pamidronsav elõállítása szulfolánban 14 Egy másik fontos, második generációs biszfoszfonát, az alendronát (19) szintézisét is megvalósítottuk szulfolánban. Az optimális mólarány esetén (3 PCl 3 :2 H 3 PO 3 ) közepes, 52%-os termelést értünk el.…”

“…18 A szulfolánban végzett kísérletek rávilágítottak, hogy az oldószernek is fontos szerepe van abban, hogy milyen reagensek vesznek részt a dronsavak képzõdésében. 14,18 Két további dronát, a benzidronát (32) és a 3-fenilpropiodronát (33) esetén váratlan eredményeket értünk el MsOH-ban. A korábbi tapasztalatainkkal ellentétben nem akkor értük el a legmagasabb termelést, amikor egyedül foszfor-trikloridot használtunk reagensként.…”

Environmentally Friendly Chemistry with Organophosphorus Syntheses in Focus

“…Based on the above reactions, we also elaborated the synthesis of ibandronate (45c) and alendronate (45d) [93]. Etidronate (45e) [94], fenidronate (45f) [95] and pamidronate (45g) [96] were also prepared in this way. The experimental data are summarized in Table 1.…”

“…The optimal ratio was 2 equivalents of phosphorous acid and 2 equivalents of phosphorus trichloride. In this case, pamidronic acid (45h) was crystallized after the hydrolysis in a yield of 63%, and in a purity of 100% (Scheme 22) [96]. …”