Treprostinil production

1. A method of preparing treprostinil or a pharmaceutically acceptable salt thereof comprising a cyclization reaction in which a compound of the formula:

is converted into a compound of the formula:

followed by hydrogenation, reaction with a reducing agent, deprotection, and conversion of a triol of formula (VIIa):

into treprostinil or a pharmaceutically acceptable salt thereof,

wherein, in each of the above formulas, P 1 and P 2 are each an independently selected alcohol protecting group;

R is —(CH 2 ) n X;

n is 0, 1, 2, or 3; and

X is phenyl substituted with one or more substituents independently selected from the group consisting of —NO 2 , —CN, halogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy.

2. The method of claim 1 , wherein P 2 is TBDMS.

3. The method of claim 1 , wherein X is phenyl substituted with (C1-C3)alkoxy,

4. The method of claim 1 , wherein Co 2 (CO) 8 is added during the cyclization reaction.

5. The method of claim 4 , wherein the cyclization reaction is carried out in a chlorinated solvent.

6. The method of claim 1 , wherein the cyclization reaction is carried out in a chlorinated solvent.

7. The method of claim 1 , wherein conversion of a triol of formula (VIIa):

into treprostinil or a pharmaceutically acceptable salt thereof is accomplished by reacting the compound represented by structural formula (VIIa) with X 1 (CH 2 ) m CN to form a compound represented by structural formula (VIII):

and

hydrolyzing the compound of Structural Formula (V) form treprostinil wherein in is 1 and X 1 is a leaving group.

8. The method of claim 1 , further comprising, prior to the cyclization reaction, reacting an aldehyde compound represented by structural formula (I):

with an alkyne compound represented by structural formula (a):

9. The method of claim 8 , wherein n is 1.