Phosphorus trichloride → Zoledronic acid monohydrate

Temperature

75 °C

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.

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 (160 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 (320 ml)
9. filtrationthe crystallized product is filtered
10. washwashed sequentially with chilled water (80 ml), acetone (80 ml)
11. dry with materialdried in air oven at 55-60° C. until water content

ORD record

ord-5bc691db8d3f4c6bbf5266e4477e1ea2

Source dataset

uspto-grants-2008_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07411087B2