Synthesis of [3H] and [2H6]AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP)

An AstraZeneca effort to identify a 5‐lipoxygenase activating protein inhibitor with good drug‐like properties resulted in the identification of AZD6642. To further understand its drug metabolism and pharmacokinetic properties, it was required labeled with tritium. The tritiation of AZD6642 was effected by Ir‐catalyzed exchange chemistry to give an average of one tritium per molecule. Additionally, a stable isotope labeled version of AZD6642 was required to support bioanalytical studies. The synthesis originated from [2H6]acetone which was converted to the trimethylsilyl cyanide adduct and subsequently reduced to give 2‐(aminomethyl)‐[1,1,1,3,3,3‐2H6]propan‐2‐ol in good yield. Carbonylation to give an amide adduct resulted in an intermediate that was converted to the final compound in four steps. Two tritium‐labeled 5‐lipoxygenase activating protein inhibitors were prepared using hydrogen isotope exchange methodology. Both compounds possessed multiple potential sites of exchange, but only exchange directed by the pyrazine was observed. Deuterium‐labeled AZD6642 was also prepared from [2H6]acetone.