Process Development of a Novel Non-Xanthine Adenosine A₁ Receptor Antagonist

Abstract

(+)−(R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453) is a novel, potent adenosine A1 receptor antagonist for the regulation of renal function. The development of a reliable process suitable for large scale manufacture is described. A Horner−Emmons reaction and a 1,3-dipolar cycloaddition were successfully scaled up to afford ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloylate, with excellent regioselectivity and stereoselectivity. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical synthesis of FK453.