Synthesis of a sodium-hydrogen exchange type 1 inhibitor: An efficient Cu-catalyzed conjugated addition of a Grignard reagent to an acetyl pyridinium salt

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.