Pilot-Scale Synthesis of a Novel Non-Xanthine Adenosine A₁ Receptor Antagonist. 1,3-Dipolar Cycloaddition of Pyridine <i>N</i>-Imine to an Acetylene

Abstract

Adenosine A1 receptor antagonist, FK838, has been synthesized in 44% overall yield by a five-step sequence which is operationally straightforward and readily carried out on a large scale. Investigations into the 1,3-dipolar cycloaddition process that afforded a pyrazolo[1,5-a]pyridine derivative are also described. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a practical and cost-effective synthesis of FK838. These methods were successfully scaled up in a pharmaceutical pilot plant to give bulk drug used in clinical trials.