3-Pyridineacetic acid → Risedronate

Participants

Reaction Conditions

Reaction Steps

A 2L cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was charged with 3-pyridine acetic acid hydrochloride (27.7 g, 0.16 mole), phosphorous acid (39.4 g, 0.48 mole) and toluene (200 ml). The suspension was heated to 90° C. Hyfllo Super-Cel diatomaceous silica (70 g, 50% w/w of all the reagents) was added in portions after the mixture of 3-pyridyl acetic acid and H3PO3 was melted, to obtain an heterogeneous suspension. Phosphorous oxychloride (44.8 ml, 0.48 mole) was then added dropwise during 12 minutes. The reaction mixture was then heated to 95° C. for 3 hours. Water (300 ml) was added after cooling the reaction mixture to 65° C. The mixture was stirred vigorously for 30 minutes and then the Hyfllo was removed by filtration. The toluene and the aqueous phases were separated and the aqueous phase was heated at 95° C. for 16 hours. The aqueous phase was cooled to 25° C. and absolute ethanol (300 ml) was added to precipitate the final product. The suspension was cooled to 5° C. for 1 hour. The white product was filtered, washed with absolute ethanol (2×80 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 31.7 g (71%) of risedronic acid monohytdrate.

Provenance & Evidence