An Efficient Undergraduate Synthesis of the Exorbitantly Priced Lambert–Eaton Myasthenic Syndrome Drug Amifampridine

An efficient synthesis of the exorbitantly priced Lambert–Eaton myasthenic syndrome drug amifampridine was developed and applied in the second-semester undergraduate organic chemistry laboratory. The two-step synthesis entails a nucleophilic aromatic substitution reaction of commercial 4-chloro-3-nitropyridine with methanolic ammonia to afford 4-amino-3-nitropyridine. Subsequent palladium-catalyzed nitro reduction provides amifampridine in high yield and purity. Amifampridine can alternatively be prepared by advanced undergraduate students in four linear steps beginning with 4-hydroxypyridine. Nitration of 4-hydroxypyridine to 4-hydroxy-3-nitropyridine and subsequent treatment with phosphoryl chloride provides the intermediate 4-chloro-3-nitropyridine, which is then subjected to the SNAr and reduction reactions to cleanly afford amifampridine without the need for column chromatography.