Phosphorus trichloride → Zoledronic acid monohydrate

Temperature

75 °C

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.

1. temperatureThe mixture is cooled to 35-40° C.
2. temperatureThe mixture is heated to 63-67° C. for 3 hrs
3. customwhereby white solid results
4. temperatureIt is then cooled to 0-5° C.
5. customquenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hr
6. temperatureThe resulting clear solution is heated at 100° C. for 3 hrs
7. temperaturecooled to ambient temperature
8. additionTo the charcoalized solution is added acetone (800 ml)
9. filtrationthe crystallized product is filtered
10. washwashed sequentially with chilled water (200 ml), acetone (100 ml)
11. dry with materialdried in air oven at 55-60° C. until water content

ORD record

ord-9a66301ea9d445c1a4ec5fc73bf7a945

Source dataset

uspto-grants-2008_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07411087B2