Processes and intermediates for the preparations of benzoprostacyclin analogues and benzoprostacyclin analogues prepared therefrom

A process for preparing a compound of Formula (R)-1″ enriched in (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess (e.e.),

• wherein X is Cl, Br, or I, the process comprising the steps of:
• (1) enantioselectively (R)-esterifying a compound of Formula 1″:
• with an acyl donor of Formula D:
• wherein R4 and R5 are independently H or C1-6 alkyl, and a first lipase, to form a mixture of (S)-alcohol and (R)-ester;
• (2) optionally removing the (S)-alcohol;
• and
• (3) deacylating the (R)-ester.

A process for preparing a compound of Formula 4:

• wherein P is H, P1 or P2;
• R2 is H or C1-4-alkyl;
• 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;
• X is Cl, Br, I, or —CH2CH2CH2COOR1, wherein R1 is C1-7-alkyl or C7-11-aralkyl;
• and P1 and P2 are protective groups for the hydroxyl groups, the process comprising the steps of:
• (1) reacting a compound of Formula 1′:
• wherein P1 and X are as defined above, with a cuprate derived from a compound of Formula L1, Formula L2, or Formula L3:
• wherein Y is Cl, Br, or I;
• P2, R2, and R3 are as defined above, to form a compound of Formula 2:
• wherein P, X, R2, and R3 are as defined above;
• (2) reducing a ketone of the compound of Formula 2 to form a compound of Formula 3:
• wherein P, X, R2 and R3 are as defined above;
• (3) performing an intramolecular cyclization reaction of the compound of Formula 3 to form a compound of Formula 4:
• wherein P, X, R2 and R3 are as defined above;
• (4) optionally performing a deprotecting reaction to remove the protective groups for the hydroxyl groups;
• and
• (5) optionally performing a Suzuki cross-coupling reaction of the compound of Formula 2, 3 or 4 wherein X is Cl, Br, or I, to form the compound of Formula 2, 3 or 4 wherein X is —CH2CH2CH2COOR1 and R1 is as defined above.