A SCALABLE SYNTHESIS OF THE THROMBOXANE RECEPTOR ANTAGONIST FONAMIDO)ETHYL]-5-(4-FLUOROBENZYL)PHENYL)PROPIONIC ACID VIA A REGIOSELECTIVE HECK CROSS-COUPLING STRATEGY

A regioselective Heck cross-coupling strategy is presented for the lar ge-scale preparation of the thromboxane receptor antagonist fonamido)e thyl]-5-(4-fluorobenzyl)phenyl}propionic acid(1). Commercially availab le 3-bromo-5-iodobenzoic acid was first converted to the corresponding acid chloride, and this was then condensed with 4-fluorobenzene via a Friedel-Crafts acylation reaction to give 3-bromo-5-iodophenyl 4-fluo rophenyl ketone. Regioselective cross coupling with ethyl acrylate and then N-vinylphthalimide, each under phosphine-free Heck conditions, l ed to formation of ethyl obenzoyl)-5-(2-phthalimidovinyl)phenyl]propen oate. Reduction of the benzophenone moiety and saturation of the olefi n double bonds, followed by phthalimide ring cleavage, then gave ethyl (2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionate monocitrate salt. This was converted to the. sulfonamido-substituted arylpropionic acid 1 via a two-step one-pot procedure in which sulfonamide formation was achieved via condensation with 4-chlorobenzenesulfonyl chloride, follo wed by ethyl ester saponification. The route described avoids hazards identified with the original medicinal chemistry based synthesis and a llows bulk quantities of drug substance to be produced for toxicologic al and clinical trials.