伊班膦酸

反应条件: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-(N-Methyl-N-pentylamino)propanoic acid hydrochloride (100 g) was suspended in toluene (300 mL) and polyethylene glycol 400 (120 mL). Phosphorous acid (43.01 g 1.1 eq.) was added to the mixture. The mixture was warmed and phosphorous trichloride (98.22 g, 1.5 eq.) was added at a rate such that the temperature remained below 60° C. The mixture was stirred for 10 hours at 55-60° C. whereupon it was quenched by adding water (450 mL). The water addition was controlled to maintain a reaction temperature below 70° C. The layers were separated and the aqueous layer was refluxed for 6 hours. The mixture was cooled to 40-45° C. to provide Ibandronic acid in solution and the pH was adjusted to 4.3-4.5 using 50% aqueous sodium hydroxide. Propylene glycol (150 mL) was then added to the reaction mixture at 60-65° C. and stirred for 4-5 hours. The mixture was cooled to 20-25° C. over a period of 2-3 hours and then for 3-4 hours at 0-5° C., filtered, washed with acetone (2×150 mL) and dried in vacuo. The mixture was warmed remained below 60° C was quenched by adding water (450 mL) The water addition to maintain a reaction temperature below 70° C The layers were separated the aqueous layer was refluxed for 6 hours The mixture was cooled to 40-45° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of amorphous ibandronic acid (5 g) in water (30 ml) was stirred at room temperature. Aqueous sodium hydroxide (0.63 g NaOH in 20 mL water) was added, and the reaction mixture was stirred at room temperature for an additional 1 hour. The solution was evaporated until dry. Hexanes (100 ml) were added to the residue and stirred for 16 hours at room temperature. The precipitate was isolated by vacuum filtration, washed with hexanes (1×50 ml), and dried in a vacuum oven at 50° C. for 45 hours to obtain 5.1 g of amorphous ibandronate sodium. The solution was evaporated until dry Hexanes (100 ml) were added to the residue stirred for 16 hours at room temperature The precipitate was isolated by vacuum filtration washed with hexanes (1×50 ml) dried in a vacuum oven at 50° C. for 45 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A slurry of amorphous ibandronic acid (5 g) in acetonitrile (200 ml) was stirred at reflux temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at reflux temperature for an additional 2 hours. Acetone (50 ml) was added dropwise. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (50 ml), and dried in a vacuum oven at 50° C. for 22 hours to obtain 3.5 g of amorphous ibandronate sodium. at reflux temperature at reflux temperature for an additional 2 hours stirred for 16 hours The precipitate was isolated by vacuum filtration washed with acetone (50 ml) dried in a vacuum oven at 50° C. for 22 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A slurry of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was stirred at room temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at room temperature for an additional 72 hours. The precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50° C. for 20 hours to obtain 5.0 g of amorphous ibandronate sodium. The precipitate was isolated by vacuum filtration dried in a vacuum oven at 50° C. for 20 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of amorphous ibandronic acid (5 g) in water (50 ml) was heated to reflux temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at reflux temperature for an additional 1 hour. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated to give 5.6 g of amorphous ibandronate sodium. to reflux temperature at reflux temperature for an additional 1 hour The clear solution was evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.55 g) in water:acetonitrile (80:20 v/v, 33 ml) was added dropwise to a solution of amorphous ibandronic acid (4 g) in water:acetonitrile (80:20 v/v, 187 ml) at reflux temperature. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dry to obtain 5.2 g of amorphous ibandronate sodium. at reflux temperature The clear solution was evaporated until dry

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.63 g) in water:IPA (80:20 v/v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:IPA (80:20 v/v, 212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 45 minutes. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dry to give 5.9 g of amorphous ibandronate sodium. at reflux temperature The reaction mixture was heated at reflux temperature for an additional 45 minutes The clear solution was evaporated until dry

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.63 g) in water:ethanol (80:20 v/v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (80:20 v/v, 212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3 hours to obtain a pH of 3.24. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dry to obtain 5.7 g of amorphous ibandronate sodium. at reflux temperature The reaction mixture was heated at reflux temperature for an additional 3 hours to obtain a pH of 3.24 The clear solution was evaporated until dry

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.58 g) in water:acetone (20:80 v/v, 9 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetone (20:80 v/v, 49 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.0. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with acetone (1×50 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 3.8 g of ibandronate sodium crystal form T. Form T can exhibit a weight loss of about 5% and about 7% in TGA. at reflux temperature The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.0 Further cooling The precipitate was filtered washed with acetone (1×50 ml) dried in a vacuum oven at 50° C. for 21 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.63 g) in water:ethanol (40:60 v/v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3.5 hours to obtain a pH of 4.03. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with ethanol (2×25 ml), and dried in a vacuum oven at 50° C. for 18 hours to give 4.9 g of ibandronate sodium crystal form S. Form S can exhibit a weight loss of about 11% to about 12%, or less in TGA. at reflux temperature The reaction mixture was heated at reflux temperature for an additional 3.5 hours to obtain a pH of 4.03 Further cooling The precipitate was filtered washed with ethanol (2×25 ml) dried in a vacuum oven at 50° C. for 18 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.63 g) in water:ethanol (60:40 v/v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (60:40 v/v, 106 ml) at room temperature. The reaction mixture was stirred at room temperature for an additional 16 hours to obtain a pH of 4.11. The white solid was filtered, washed with ethanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R. to obtain a pH of 4.11 The white solid was filtered washed with ethanol (2×25 ml) dried in a vacuum oven at 50° C. for 21 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (0.63 g) in water:methanol (40:60 v/v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:methanol (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.04. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with methanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R. at reflux temperature The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.04 Further cooling The precipitate was filtered washed with methanol (2×25 ml) dried in a vacuum oven at 50° C. for 21 hours