Process Improvements in the Production of a Novel Non-Xanthine Adenosine A1 Receptor Antagonist. A “One-Pot” Horner-Emmons Isomerization Reaction

Abstract

Pilot plant scale synthesis of 2-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl-1(6H)-pyridazin-6-one)-1-cyclohexen-1-yl] acetic acid (FR166124) is described. The process involved efficient isomerization of regioisomers produced in a Horner-Emmons reaction and employed ester exchange and hydrolysis with NaOH in MeOH. Challenges encountered in the final purification stage to afford high quality drug substance in pure crystalline form are also described. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical, and cost-effective synthesis of FR166124. These methods were successfully scaled up in a pilot plant to give bulk drug suitable for pharmacological and toxicological evaluation.