Zoledronic acid hydrate synthesis

118072-93-8

165800-06-6

The general procedure for the synthesis of 1-hydroxy-2-(1-imidazolyl)ethane-1,1-diphosphonic acid hydrate from (1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diphosphonic acid is as follows: Example 3: Preparation of zoledronic acid monohydrate The pristine moist zoledronic acid (equivalent to 90.3 g of crude product) obtained according to Example 1 was suspended in 3050 ml of water. The suspension was heated to reflux under stirring conditions. Subsequently, EPO water was added to bring the total volume to 3750 ml until complete dissolution. The heating was stopped and stirring was continued to allow the solution to cool slowly to room temperature. When the internal temperature dropped to about 70-80°C, it was further cooled to 2-5°C and maintained at this temperature for 1 hour. The precipitate was filtered and washed with ice water. The resulting precipitate was dried in an airflow oven. Finally, 169.3 g (89% yield) of colorless crystals were obtained at 5°C to 60°C. The loss of water of crystallization was measured to be 6.8% by thermogravimetric analysis (TGA), confirming the monohydrate. The X-ray powder diffraction (XRPD) pattern of the substance showed characteristic peaks at 2θ values of 12.1°, 12.8°, 15.7°, and 18.9° ± 0.2°, which is consistent with the diffraction data of the known crystalline type I (US 2005/0054616). Figure 1A illustrates its XRPD pattern, while Figure IV shows the arrangement structure of the atoms in the crystal cell.