Methods of manufacturing treprostinil and treprostinil derivative prodrugs

Abstract

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 C5-C18 alkyl, branched C5-C18 alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-C1-C18 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 .- 31 . (canceled) 
     
     
         32 . A method for making a treprostinil prodrug having the following formula: 
       
         
           
           
               
               
           
         
         comprising, 
         mixing, in the presence of an acid catalyst, a compound of Formula (A) with an alcohol of the formula R 2 —OH, wherein R 2  is a linear or branched C 5 -C 18  alkyl, a linear C 2 -C 18  alkenyl or a branched C 3 -C 18  alkenyl, aryl, aryl-C 1 -C 18  alkyl, an amino acid or a peptide, 
         incubating the mixture for a sufficient period of time to form the compound of Formula (A). 
       
     
     
         33 .- 53 . (canceled)