Synthesis of a Sodium–Hydrogen Exchange Type 1 Inhibitor: An Efficient Cu-Catalyzed Conjugated Addition of a Grignard Reagent to an Acetyl Pyridinium Salt

Abstract

A facile and economical five-step process for the synthesis of a sodium–hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient palladium-catalyzed carbonylation of aryl bromides, and a high-yielding acyl guanidine formation. A safe and scalable protocol for preparation of 2-trifluoromethyl phenyl Grignard reagent was developed, and a facile method for controlling the palladium content with N-acetyl-L-cysteine as the scavenger was demonstrated. Process issues in controlling the formation of a key diacylation side product during acyl guanidine formation are also addressed.