A modified approach to C-14-labeled 2-(3,4-difluorophenoxy)-5-fluoronicotinic acid and other halogen-substituted analogs

A modified approach to a carbon‐14‐labeled pyridine ring system was developed based on the electrocyclic ring‐closure of 1,4,4‐trisubstituted butadiene. The new method was applied to prepare 2‐(3,4‐difluorophenoxy)‐5‐fluoro‐[2‐14C] nicotinic acid and other halogen‐substituted analogs. The targeted compound was isolated with a radiochemical purity of >98% and a specific activity of 53 mCi/mmol from four radiochemical steps, starting from ethyl [1‐14C] cyanoacetate in an overall radiochemical yield of 39%. Copyright © 2011 John Wiley & Sons, Ltd. 2‐(3,4‐Difluorophenoxy)‐5‐fluoronicotinic acid is a key intermediate in the synthesis of a Pfizer drug candidate. A modified approach to the synthesis of a carbon‐14‐labeled pyridine ring system was developed based on the electrocyclic ring‐closure of 1,4,4‐trisubstituted butadiene and applied to prepare the target compound and other halogen‐substituted analogs. The yield for O‐arylation of 2‐chloronicotinate with 3,4‐difluorophenol was also improved by utilizing a palladium catalyst or Barton's base. The radio‐synthesis of 2‐(3,4‐difluorophenoxy)‐5‐fluoro‐[2‐14C]nicotinic acid started with ethyl [14C]cyanoacetate was prepared in an overall radiochemical yield of 39%. The details of this synthesis will be presented. Copyright © 2011 John Wiley & Sons, Ltd.