A Practical Synthesis of the Platelet Fibrinogen Antagonist, Elarofiban

Abstract

Elarofiban is a novel, nonpeptide, orally active fibrinogen receptor antagonist useful for the treatment of platelet mediated thrombotic disorders (Costanzo, M. J.; Hoekstra, W. J.; Maryanoff, B. E. WO, 97/41102, 1997). Herein we describe the process research that was carried out for the synthesis of elarofiban that eventually led to the development of a safe and cost-effective commercial scale process.

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…[104] The application of asymmetric hydrogenation to the preparation of enantiopure b-amino acids would appear to be a logical solution. However, the preparation of b-amino acids continues to rely principally on the resolution of racemates [105] or on the use of chiral auxilaries. [106] The application of catalytic asymmetric hydrogenation has been hindered by the assumption that protection of the nitrogen atom is required to achieve high levels of selectivity by virtue of the formation of a six-membered ring chelate between the substrate and the metal.…”

Practical Tactics in Resolution of Racemates via Diastereomeric Salt Formation

“…The resolution of (±)-ethyl nipecotate (1) (Scheme 1) with both optically active tartaric acids was reported. 13 Recrystallization of the diastereomeric salts was carried out from aqueous i-PrOH solvent, 14 (＋)-diastereomeric L-tartrate salt was first obtained in 23.1% yield and, then, (-)-diastereomeric D-tartrate salt was in 26.9% yield from the recovered mother liquor.…”

Chemoselektivität und die eigentümlichen Reaktivitäten funktioneller Gruppen

“…Die Anwendung asymmetrischer Hydrierungen zur Herstellung enantiomerenreiner β‐Aminosäuren erscheint als logischer Schritt. Allerdings basieren gängige Synthesen von β‐Aminosäuren bislang weiterhin auf der Racematspaltung105 oder der Verwendung chiraler Auxiliare 106. Bezüglich einer katalytischen asymmetrischen Hydrierung bestand bisher die Annahme, dass eine hohe Selektivität (vermittelt durch die Bildung eines sechsgliedrigen Chelatrings zwischen Substrat und Metall) eine Schützung des Stickstoffs erfordert.…”