Processes and intermediates for the preparation of carbaprostacyclin analogues

A process for preparing compound of Formula 4:

• wherein Y is —CH2OP or —COOR1;
• P is H or a hydroxyl protective group;
• R1 is C1-7-alkyl, aryl or aralkyl, each of which is unsubstituted or substituted by C1-4-alkyl, C2-7-alkenyl, C2-7-alkynyl, nitro, halogen or alkoxy;
• R2 is H or C1-4-alkyl;
• and R3 is C1-7-alkyl, C2-7-alkynyl, aryl or aryloxy, each of which is unsubstituted or substituted by C1-4-alkyl, halogen, or trihalomethyl, the process comprising the steps of:
• (1) reacting a starting compound of Formula 1:
• wherein X is F, Cl, Br, I, or —OTs;
• P1 is a hydroxyl protective group;
• and Y is as defined above, with a starting cuprate derived from a compound of Formula L1, Formula L2, or Formula L3:
• wherein X1 is Cl, Br, or I;
• P2 is a hydroxyl protective group;
• and R2 and R3 are as defined above, to form a compound of Formula 2:
• wherein P, X, Y, R2 and R3 are as defined above;
• (2) methylenation of a ketone radical of the compound of Formula 2 to form a compound of the following formula 3:
• wherein P, X, Y, R2 and R3 are as defined above;
• (3) performing an intramolecular cyclization reaction to the compound of Formula 3 to form the compound of Formula 4:
• wherein P, Y, R2 and R3 are as defined above;
• and
• (4) optionally performing a deprotecting reaction for removing P1 and/or P2.