Phosphorus trichloride → Zoledronic acid monohydrate

Participants

Reaction Conditions

Reaction Steps

A suspension of 1-imidazolylacetic acid (50 g, 0.396 mol) and phosphorous acid (48.7 g, 0.594 mol) in sulfolane (180 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (117 ml, 1.346 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hrs, whereby white solid results. It is then cooled to 0-5° C. and quenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hr. The resulting clear solution is heated at 100° C. for 3 hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (800 ml). The mixture is then stirred for 4 hrs at 20-25° C. and the crystallized product is filtered, washed sequentially with chilled water (200 ml), acetone (100 ml) and dried in air oven at 55-60° C. until water content is between. 6.2-7.2% w/w. Yield 81.3 g, (70.7%), appearance: white crystalline solid.

Provenance & Evidence