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.
Graphical abstract
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Acknowledgements
One of the authors (Ramesh Goura) thanks to the Maithri Drugs Pvt. Ltd for giving opportunity to pursue Ph.D. Our sincere thanks to Dr. Ch. Nagaraju for providing infrastructural facilities to carry out the research work, and also be indebted to Dr. Anil Kumar Muthyala, Dr. Vijayalaxmi Chapala and Udaya Sagar Gavini for their continuous guidance and support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Notes
1 MDPL-TC Communication No. 001.