Process for treprostinil salt preparation
Disclosed is a process for preparing a treprostinil salt. The process involves the step of dissolving treprostinil in a water-miscible organic solvent to form a treprostinil solution. The treprostinil solution is reacted with an aqueous basic solution containing an alkali metal cation to form treprostinil salt. Allowing crystallization of the treprostinil salt to take place, and then collecting the treprostinil salt formed.
1. A process for preparing a treprostinil salt, comprising:
dissolving treprostinil in a solvent, wherein the solvent consists essentially of a water-miscible organic solvent, to form a treprostinil solution, wherein the water-miscible organic solvent is selected from a water-miscible ketone, a water-miscible ether or acetonitrile;
reacting the treprostinil solution with an aqueous basic solution containing an alkali metal cation to form a reaction mixture containing the treprostinil salt;
allowing crystallization of the treprostinil salt; and
collecting the treprostinil salt formed.
2. The process according to claim 1 , wherein the water-miscible organic solvent is a hydrocarbon based water-miscible ketone solvent.
3. The process according to claim 1 , wherein the water-miscible ketone solvent is a linear or branched alkyl ketone.
4. The process according to claim 1 , wherein the water-miscible ketone solvent is acetone.
5. The process according to claim 1 , wherein the water-miscible organic solvent is tetrahydrofuran.
6. The process according to claim 1 , wherein ratio of treprostinil to the water-miscible organic solvent is 1 g of treprostinil to from 5 to 100 mL of the water-miscible organic solvent.
7. The process according to claim 1 , wherein ratio of treprostinil to the water-miscible organic solvent is 1 g of treprostinil to from 15 to 50 mL of the water-miscible organic solvent.
8. The process according to claim 1 , wherein the aqueous basic solution contains hydroxide, carbonate or bicarbonate anion.
9. The process according to claim 1 , wherein the alkali metal cation is lithium, sodium or potassium.
10. The process according to claim 1 , wherein the alkali metal cation is sodium.
11. The process according to claim 1 , wherein the aqueous basic solution contains sodium hydroxide.
12. The process according to claim 1 , wherein the base in the aqueous basic solution has a concentration of from about 2 to about 8 molar.
13. The process according to claim 1 , wherein the base in the aqueous basic solution has a concentration of about 5 molar.
14. The process according to claim 1 , wherein mole ratio of base in the aqueous basic solution to treprostinil ranges from 1:1 to 2:1.
15. The process according to claim 1 , wherein mole ratio of base in the aqueous basic solution to treprostinil is about 1.1:1.
16. The process according to claim 1 , wherein volumetric ratio of the water-miscible organic solvent to the aqueous basic solution is from 10:1 to 70:1.
17. The process according to claim 1 , wherein volumetric ratio of the water-miscible organic solvent to the aqueous basic solution is about 40:1.
18. The process according to claim 1 , wherein the treprostinil salt is treprostinil sodium.
19. The process according to claim 1 , further comprising warming the treprostinil solution up to about 60° C. prior to reacting it with the aqueous basic solution.
20. The process according to claim 1 , further comprising warming the treprostinil solution up to about 30° C. prior to reacting it with the aqueous basic solution.
21. The process according to claim 1 , wherein the aqueous basic solution is added to the treprostinil solution for reaction therewith.
22. The process according to claim 1 , wherein the reaction of the treprostinil solution with the aqueous basic solution is carried out at an internal temperature below about 60° C.
23. The process according to claim 1 , wherein the reaction of the treprostinil solution with the aqueous basic solution is carried out at an internal temperature below about 30° C.
24. The process according to claim 1 , wherein the reaction of the treprostinil solution with the aqueous basic solution is agitated.
25. The process according to claim 1 , wherein after allowing crystallization of treprostinil salt, the reaction mixture is agitated for at least about 4 hours.
26. The process according to claim 1 , wherein after allowing crystallization of the treprostinil salt, the reaction mixture is agitated for about 1 hour.
27. The process according to claim 25 , wherein the agitation is carried out at room temperature.
28. The process according to claim 1 , further comprising cooling the reaction mixture from 0 to 15° C. prior to collecting the crystals.
29. The process according to claim 1 , further comprising cooling the reaction mixture from 0 to 5° C. prior to collecting the crystals.
30. The process according to claim 28 , further comprising agitating the reaction mixture during cooling.
31. The process according to claim 30 , wherein the solution is cooled and agitated for about 5 hours.
32. The process according to claim 31 , wherein the solution is cooled and agitated for about 1 hour.
33. The process according to claim 1 , wherein the treprostinil salt is collected by vacuum filtration.
34. The process according to claim 1 , wherein the treprostinil salt collected is dried.