Phosphorus trichloride → Zoledronic acid monohydrate

Participants

Reaction Conditions

Reaction Steps

A suspension of 1-imidazolylacetic acid (20 g, 0.159 mol) and phosphorous acid (19.6 g, 0.239 mol) in 1,2-dimethoxyethane (72 ml) is heated to 75° C. for 30 minutes. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (48 ml, 0.543 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 (160 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 (320 ml). The mixture is then stirred for 4 hours at 20-25° C., the crystallized product is filtered, washed sequentially with chilled water (80 ml), acetone (80 ml) and dried in air oven at 55-60° C. until water content is between 6.2-7.2% w/w. Appearance: white crystalline solid, purity >99.5%, meeting specification as per IHS.

Provenance & Evidence