Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Abstract

A practical and efficient process was developed for the manufacture of a positive allosteric modulator (PAM) of the α7 nicotinic acetylcholine receptor via an eight-step synthetic route that furnished a high-quality active pharmaceutical ingredient. Highlights of this synthesis include (1) a highly reproducible palladium-catalyzed cyanation; (2) reduction in the number of steps by revisiting the original protection/deprotection strategy; (3) avoidance of the use of halogenated solvents in all of the steps; (4) replacement of reagents that had procurement issues, such as N-phenyltrifluoromethanesulfonimide and Ghosez's reagent, with more commonly used reagents; and (5) no chromatographic purification in any step. This highly efficient process was successfully demonstrated on a pilot scale to yield up to 63.5 kg of the active pharmaceutical ingredient.