Methods for producing Beraprost and its derivatives

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;
• R1 is an alkyl, cycloalkyl or TBDMS;
• R2 is independently H or an alcohol protecting group;
• R3 is a straight or branched alkyl group having 1-4 carbon atoms;
• and
• R6 is an alcohol protecting group.