Methanol → Zoledronate disodium tetrahydrate

HRID 733468Notes

Reaction equation

HRID 733468 reaction equation
[OH-:1].[Na+:2].CO.[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:17]([OH:20])([OH:19])=[O:18])([P:13]([OH:16])([OH:15])=[O:14])[OH:12])[CH:6]=1>O>[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:13]([O-:16])([OH:15])=[O:14])([P:17]([O-:19])([OH:20])=[O:18])[OH:12])[CH:6]=1.[OH2:1].[OH2:12].[OH2:12].[OH2:12].[Na+:2].[Na+:2]

Participants

5

Reactant 3

HCID 887Methanol2×HCID 14798Sodium HydroxideHCID 68740Zoledronic Acid

Product 1

HCID 23649597Zoledronate disodium tetrahydrateYield 97%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Procedure

A solution of sodium hydroxide (1.4 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form I) (10 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 17 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (1×10 ml) and dried in a vacuum oven at 50° C. for 26 hours to give 5.6 g (97%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.4%). Purity by HPLC 99.9%.

Workup

  1. additionwas added drop-wise
  2. temperatureat reflux temperature
  3. temperatureThe reaction mixture was heated
  4. temperatureat reflux temperature for additional 17 hours
  5. temperatureFurther cooling
  6. filtrationThe precipitate was then filtered
  7. washwashed with Methanol (1×10 ml)
  8. customdried in a vacuum oven at 50° C. for 26 hours

Sources & evidence

ORD record
ord-18f1eb03b8474a5f83f5d8967ef5151d
Source dataset
uspto-grants-2009_09
Patent number
US07589211B2

Reaction notes

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