Hydrochloric Acid → Treprostinil

Participants

Reaction Steps

A 3.4-kg sample of treprostinil diethanolamine salt was dissolved in 36 L of sterile water, 60 L of ethyl acetate and 3.6 L of 3 M HCl were added and the mixture stirred. The layers were separated and the aqueous layer was extracted thrice with 20-L portions of ethyl acetate. The four organic layers were combined, the organic solution washed twice with 20-L portions of sterile water, once with 20 L of brine and dried over 2.86 kg of anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to yield treprostinil as a gummy solid. This solid was transferred to glass drying trays and let air-dry for 66 hours. This solid was then dissolved in 23.8 kg of ethanol, warmed to 48° C. and treated with 23.8 kg of warm (40-50° C.) sterile water. The solution was stirred and then stirring was stopped to allow the treprostinil to slowly crystallize. The resulting white solid was collected by filtration in an Aurora filter, washed with 45 L of a cold (6° C.) 20% ethanol in sterile water solution, the filter moved to a Hepa-filtered Finishing Room and the solid dried under house vacuum for 23 hours. The solid was transferred to glass drying trays and further air-dried for 115 hours until the total weight of the material was constant (no further solvent loss). A sample of this treprostinil monohydrate was taken as Lot #D-1007-089 for stability studies. The remaining material was further dried in a vacuum oven at 55° C. and 1.66 Torr for 10 hours to give 2.68 kg (96.4%) of anhydrous treprostinil (Lot #01G07018).

Provenance & Evidence