A Scalable Synthesis of the Thromboxane Receptor Antagonist 3-{3-[2-(4-Chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic Acid via a Regioselective Heck Cross-Coupling Strategy

Abstract

A regioselective Heck cross-coupling strategy is presented for the large-scale preparation of the thromboxane receptor antagonist 3-{3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic acid (1). Commercially available 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-fluorophenyl ketone. Regioselective cross-coupling with ethyl acrylate and then N-vinylphthalimide, each under phosphine-free Heck conditions, led to formation of ethyl 3-[3-(4-fluorobenzoyl)-5-(2-phthalimidovinyl)phenyl]propenoate. Reduction of the benzophenone moiety and saturation of the olefin double bonds, followed by phthalimide ring cleavage, then gave ethyl 3-[3-(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, followed by ethyl ester saponification. The route described avoids hazards identified with the original medicinal chemistry based synthesis and allows bulk quantities of drug substance to be produced for toxicological and clinical trials.

Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

“…Waite and Mason at Pfizer in the U.K. reported the synthesis of 358 , a potent thromboxane receptor antagonist for the treatment of asthma, unstable angina, deep vein thrombosis, and coronary atherosclerosis (Scheme ) . By taking advantage of the difference in reactivity between aryl iodides and aryl bromides under Heck reaction conditions, the researchers coupled 353 and ethyl acrylate ( 354 ) chemoselectively at the iodide of 353 in MeCN at reflux.…”

Critical Assessment of Pharmaceutical ProcessesA Rationale for Changing the Synthetic Route

“…Other examples of changing the synthetic route to achieve control over residual impurities 95 and nonselective reactions 96 and to introduce crystalline control points 30 have been reported in the literature.…”

Practical Synthesis of A Macrocyclic HCV Protease Inhibitor: A High-Yielding Macrolactam Formation

“…Oxidation of the aldehyde 15 to the methyl ester 16 with iodine and NaOMe established the correct oxidation state . Introduction of the other two carbons for the isoquinoline was accomplished by Heck reaction of N -vinyl phthalimide . This reaction was regioselective toward the terminal carbon to give 17 : 18 in 9:1 ratio based on NMR of the reaction mixture.…”