Hydrochloric Acid → Treprostinil

HRID 1803472Notes

Reaction equation

HRID 1803472 reaction equation
[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:28])[CH2:7][CH2:8][C@@H:9]1[C@H:13]2[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[CH2:17][C@H:12]2[CH2:11][C@H:10]1[OH:27].C(NCCO)CO.C(OCC)(=O)C.Cl>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:28])[CH2:7][CH2:8][C@H:9]1[C@H:10]([OH:27])[CH2:11][C@H:12]2[C@@H:13]1[CH2:14][C:15]1[C:16]([CH2:17]2)=[C:18]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 8857Ethyl AcetateHCID 11179459Treprostinil diolamine

Product 1

HCID 6918140Treprostinil

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

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).

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted thrice with 20-L portions of ethyl acetate
  3. washthe organic solution washed twice with 20-L portions of sterile water, once with 20 L of brine
  4. dry with materialdried over 2.86 kg of anhydrous sodium sulfate
  5. filtrationThe mixture was filtered
  6. concentrationthe filtrate was concentrated

Sources & evidence

ORD record
ord-c9c4102c8eb6424798de371b4712c1d3
Source dataset
uspto-grants-2013_01
Patent number
US08350079B2

Reaction notes

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