Methods of manufacturing treprostinil and treprostinil derivative prodrugs
Methods for making prodrugs of treprostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C 5 -C 18 alkyl, branched C 5 -C 18 alkyl, linear C 2 -C 18 alkenyl, branched C 3 -C 18 alkenyl, aryl, aryl-C 1 -C 18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.
1. A method for making a treprostinil prodrug having the following formula:
comprising,
mixing, in the presence of an acid catalyst, treprostinil with an alcohol of the formula R 2 —OH, wherein R 2 is a linear C 14 -C 18 alkyl,
incubating the mixture for a sufficient period of time to form the compound of Formula (A).
2. The method of claim 1 , wherein the treprostinil is dissolved in a solvent prior to mixing with the acid catalyst.
3. The method of claim 2 , wherein the solvent comprises dioxane.
4. The method of claim 2 , wherein the solvent comprises acetonitrile (MeCN), N,N′-dimethylformamide (DMF), dichloromethane (DCM), or a combination thereof.
5. The method of claim 2 , wherein the solvent comprises 2 mL of dioxane per 100 μmol of treprostinil, 1 mL of dioxane per 100 μmol of treprostinil, DMF, DCM, MeCN, 1:1 dioxane:MeCN, DMF/DCM, 10% DMF/DCM, or 20% DMF/DCM.
6. The method of claim 1 , wherein the acid catalyst is a solid.
7. The method of claim 6 , wherein the solid is a solid resin.
8. The method of claim 1 , wherein the acid catalyst comprises sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene sulfonate, heteropoly acid, zeolites, metal oxides, graphene oxygen or a combination thereof.
9. The method of claim 1 , wherein R 2 is linear hexadecyl.
10. The method of claim 1 , wherein the acid catalyst is a sulfonic acid resin.
11. The method of claim 10 , wherein R 2 is linear hexadecyl.
12. The method of claim 11 , wherein the treprostinil is dissolved in a solvent prior to mixing with the acid catalyst.
13. The method of claim 12 , wherein the solvent comprises dioxane.
14. The method of claim 1 , wherein R 2 is linear tetradecyl.
15. The method of claim 1 , wherein R 2 is linear pentadecyl.
16. The method of claim 1 , wherein R 2 is linear heptadecyl.
17. The method of claim 1 , wherein R 2 is linear octadecyl.