Improved and ‘Nitrosamines Free’ Process for the Preparation of an α4β2 Neuronal Nicotinic Acetylcholine Receptor Agonist-Varenicline Tartrate

Abstract

An improvised and efficient approach for synthesis of α4β2 nicotinic acetylcholine receptor subtype agonist, Varenicline tartrate (1) free from the ‘N-nitrosamines’ has been described. The approach involves an improved process for a key intermediate (7,8-dinitro-4,5-dihydro-1H-1,5-methanobenzo[d] azepin-3(2H)-yl)-2,2,2-trifluoro ethanone (7) free from potential genotoxic impurities. Compound 7 is converted into Varenicline base 10 in a single pot process with improved overall yield and quality. Further, Varenicline base 10 is converted into Varenicline tartrate (1) by acid addition salt which provides in quantitative yield. Our improved process consists of technical innovations/improvements which eliminate the probability for the formation of critical impurities such as dinitro nitroso impurity 2, diamino nitroso impurity 3 and varenicline nitroso impurity 4 and other genotoxic impurities such as mono nitro impurity 11 and meta dinitro impurity 12 in the final drug substance and provides ‘Nitrosamines free’ varenicline tartrate (1) with good quality and yield.