Isopropanol → Zoledronate disodium tetrahydrate

HRID 730599Notes

Reaction equation

HRID 730599 reaction equation
[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-:17].[Na+:18].[Na].CC([OH:23])C>O>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([OH:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[OH2:23].[OH2:17].[OH2:8].[OH2:8].[Na+:18].[Na+:18]

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 14798Sodium HydroxideHCID 68740Zoledronic AcidHCID 5360545Sodium

Product 1

HCID 23649597Zoledronate disodium tetrahydrate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
80 °C

Procedure

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser was loaded with Zoledronic acid form I (10.0 g) and water (260 ml). The suspension was heated to 80° C. to obtain a clear solution. Sodium hydroxide (pearls, 2.84 g) was added. A pH test of the sodium salt showed pH=7.35. The solution was cooled to 60° C. and IPA (10.5 ml) was added. The reaction mixture was cooled to room temperature during 2 hours and was stirred at this temperature for about 16 hours. After cooling to 5° C. and stirring at this temperature for 2 hours, the solution was evaporated to dryness to obtain a white solid. The obtained solid was reslurried in water (50 ml) and cooled to 4° C. The product was then isolated by filtration and dried in a vacuum oven at 50° C. for 24 hours to obtain 3.2 g of Zoledronate disodium crystal form VII (24%) (pH=7.27). Purity by HPLC 100.0%.

Workup

  1. customA 0.5 liter reactor equipped with a mechanical stirrer
  2. customto obtain a clear solution
  3. temperatureThe solution was cooled to 60° C.
  4. temperatureThe reaction mixture was cooled to room temperature during 2 hours
  5. temperatureAfter cooling to 5° C.
  6. stirringstirring at this temperature for 2 hours
  7. customthe solution was evaporated to dryness
  8. customto obtain a white solid
  9. temperaturecooled to 4° C
  10. customThe product was then isolated by filtration
  11. customdried in a vacuum oven at 50° C. for 24 hours

Sources & evidence

ORD record
ord-72617edf3f784ae7927d1f6aab93f7fa
Source dataset
uspto-grants-2009_09
Patent number
US07582768B2

Reaction notes

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