Zaklady Farmaceutyczne Polpharma S.a.

Robert Rynkiewicz

Slawomir Makowiec

Leszek Dembkowski

Roman Szramka

Janusz Rachon

Marcin Szulc

Mariusz Krzyzanowski

Witold Przychodzeń

Janusz Rachoń

Zdzislaw Roznerski

Dariusz Witt

Jerzy Drygas

Daniel Zyla

The method of synthesizing vardenafil base, in anhydrous conditions, by chlorosulfonation of 2-(2-etoxy-phenyl)-5 -methyl-7-propyl-iH-imidazo[5,1-fJ[1,2,4]triazin-4-one in a mixture of thionyl chloride and sulfurochloridic acid followed by amidation of the product, 4-etoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzene-sulfonic acid chloride with N-ethylpiperazine, in an aprotic solvent, in the presence of an inorganic base and the method of conversion the product, vardenafil base, to yield vardenafil monohydrochloride trihydrate having a melting point of 234&#xb0; C. by contacting with water of the anhydrous modification V of vardenafil monohydrochloride in an organic solvent. The subject of the invention is also the anhydrous modification V of vardenafil monohydrochloride and its use in the preparation of vardenafil monohydrochloride trihydrate having a melting point of 234&#xb0; C.

Method for manufacturing of vardenafil and its salts

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.

[object Object]

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

Growing community of inventors

Starogard Gdanski, Poland

Robert Rynkiewicz