Methods for producing Beraprost and its derivatives

1. A method of preparing a compound represented by the structural Formula (I):

and salts thereof; comprising:

(a) reacting a substituted halophenol with 6-oxabicyclo[3.1.0]hex-2-ene in presence of a palladium catalyst to form an ether compound represented by structural Formula (III):

(b) acetylating the ether compound of Formula (III) to form a compound of Formula (IV)

(c) allylating the compound of Formula (IV) with allyltributylstannane in presence of AIBN to form the allylation product (V)

(d) subjecting the terminal alkene compound of Formula (V) to intermolecular allylic acetoxylation to form a compound of Formula (VI)

(e) subjecting the compound of Formula (VI) to dihydroxylation to form a compound of Formula (VII)

(f) subjecting the dihydroxy compound (VII) to oxidation to form an aldehyde compound of Formula (VIII)

(g) reducing the aldehyde compound of Formula (VIII) and removing the acetyl group to provide the diol compound of Formula (IX); and

(h) converting the diol of Formula (IX) to a protected aldehyde of Formula (VIIIA); and

(i) reacting the protected aldehyde of Formula (VIIIA) with a phosphonate of Formula (X) to obtain a compound of Formula (I)

wherein:

X is F, Cl, Br or I;

R 1 is an alkyl, cycloalkyl or TBDMS;

R 2 is independently H or an alcohol protecting group;

R 3 is a straight or branched alkyl group having 1-4 carbon atoms; and

R 6 is an alcohol protecting group.

2. The method of claim 1 , wherein R 1 is methyl or ethyl.

3. The method of claim 1 , wherein the palladium catalyst is PdCl 2 (PPh 3 ) 2 .

4. The method of claim 1 , wherein the allylation reaction is carried out in the presence of an allylating reagent.

5. The method of claim 1 , wherein the allylic acetoxylation reaction is carried out in the presence of acetic acid and PdCl 2 catalyst.

6. The method of claim 1 , wherein the catalytic dihydroxylation is carried out in the presence of N-methylmorpholine N-oxide (NMO) oxidant and a catalytic amount of OsO 4 .

7. The method of claim 1 , wherein the dihydroxy compound (VII) is oxidized in the presence of a periodate compound.

8. The method of claim 1 , wherein the transition metal catalyst is a hydride of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof or a carbonyl hydride complex of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof.

9. The method of claim 1 , wherein the transition metal catalyst is a ruthenium hydride complex.

10. The method of claim 1 , wherein the transition metal catalyst carbonylchlorohydridotris(triphenylphosphine)ruthenium(II).