Synthesis And Impurity Profile Study Of A Class Of Agents Known As Selective Neuronal Potassium Channel Openers

In the field of cell biology, potassium channels are the most widely distributed typeof ion channel and are found in virtually all living organisms. They formpotassium-selective pores that span cell membranes. Furthermore potassium channelsare found in most cell types and control a wide variety of cell functions.Flupirtine is the prototype of a new class of drug: the selective neuronal potassiumchannel opener (SNEPCO) which is used as an analgesic for acute and chronic pain, inmoderate to severe cases. It is unique as a non-opioid, non-NSAID and non-steroidalanalgesic. Retigabine is a close structural analog of the centrally-acting analgesicflupirtine. It is an antiepileptic drug with a recently described novel mechanism ofaction that involves opening of neuronal KV7.2–7.5(formerly KCNQ2–5)voltage-activated K+channels.In this paper, a five-step procedure and optimization for synthesis of flupirtinemaleate pure products was described.6-chloro-3-nitropyridin-2-amine as startingmaterial reacted with4-fluorobenzylamine to give2-amino-3-nitro-6-(4-fluorbenzylamino)-pyridine, after catalytic hydrogenation, acylated by ethylchloroformate and salified with maleic acid, crud flupirtine maleate were formed. Afterpurification and transformation during crystallization, stable modification A wasobtained with high yield and purity. Crystallizates of flupirtine maleate obtained fromisopropanol were examined by X-ray diffractometer, thermoanalysis and IR. DuringFT-IR analysis, it is found the transformation mixture method of modification A and Bto pure modification A.Besides, a three-step procedure and optimization for synthesis of retigabine pureproduct was described refer to the synthetic route of flupirtine. Chemical structures ofintermediates and final product were characterized using NMR (1H,13C), MS and IRtechnics.Additionally, impurity profile of flupirtine and retigabine have been studied. Twoprocess related impurities (Impurity A and B) and two degradation impurities (ImpurityC and D) of flupirtine have been synthesized, three process related impurities (ImpurityE, G and H) and two degradation impurities (Impurity F and I) of retigabine have beensynthesized. These nine impurities were synthesized using simple and efficient methods.Chemical structural of these impurities were characterized by NMR (1H,13C), MS, andIR spectral data.2D NMR (HMBC, NOESY) experiments were performed in order toanalyze the isomers of impurity-A, B, E and G. To the best of our knowledge, impurityA, B, G, and H were first reported in this paper.