Phosphorus trichloride → Ibandronate

Temperature

57.5 °C

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.

1. temperatureThe mixture was warmed
2. customremained below 60° C
3. customwas quenched
4. additionby adding water (450 mL)
5. additionThe water addition
6. temperatureto maintain a reaction temperature below 70° C
7. customThe layers were separated
8. temperaturethe aqueous layer was refluxed for 6 hours
9. temperatureThe mixture was cooled to 40-45° C.

ORD record

ord-baeb34ab85334fa380b7e57f72d9b7cf

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07696183B2