Zaklady Farmaceutyczne Polpharma S.a.

Leszek Dembkowski

Robert Rynkiewicz

Slawomir Makowiec

Janusz Rachon

Roman Szramka

Zdzislaw Roznerski

Janusz Rachoń

Witold Przychodzeń

Daniel Zyla

Dariusz Witt

Mariusz Krzyzanowski

A process for the preparation of [1-hydroxy-2-(1-imidazol-1-yl)-ethylidene]bisphosphonic acid consists of the reaction of aqueous solution of 1H-imidazole-1-acetic acid hydrochloride with phosphorus trichloride followed by removal of the excess of phosphorus trichloride, addition of water and hydrolysis of the reaction products. In order to isolate the product the post-reaction mixture is filtered and the anti-solvent is added to the aqueous filtrate in order to crystallize out [1-hydroxy-2-(1-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate.

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The invention relates to a novel process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid and hemipentahydrate monosodium salt thereof comprising (a) reacting an aqueous solution of 3-pyridyl acetic acid hydrochloride with phosphorus trichloride; (b) removing unreacted phosphorus trichloride; (c) adding water and hydrolyzing; (d) isolating crystalline [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid; (e) suspending said crystalline [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid in water; (f) adding sodium hydroxide, filtering off, and washing; and (g) drying obtained hemipentahydrate monosodium salt of 1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid.

Process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethylidene] bisphosphonic acid and hemipentahydrate monosodium salt thereof

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Pruszcz Gdanski, Poland

Leszek Dembkowski