伊班膦酸杂质2

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:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 68.8 g (367.4 mmol) N-methyl-N-pentyl-β-alanine methyl ester was hydrolyzed by refluxing with 138 ml water. Then the water is partly distilled off and 83 ml (472.7 mmol) hydrochloric acid (19%) was added. Water was distilled off again and 230 ml methyl ethyl ketone was added to remove residual water by azeotropic distillation. The reaction mixture was then cooled to 24° C. The crystallized product was separated and washed with methyl ethyl ketone and subsequently dried in vacuo. 63.7 g (82.7%) N-methyl-N-pentyl-β-alanine hydrochloride were obtained. Then the water is partly distilled off Water was distilled off again 230 ml methyl ethyl ketone was added to remove residual water by azeotropic distillation The crystallized product was separated washed with methyl ethyl ketone subsequently dried in vacuo

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.