Production of Nicotine and Varenicline

Nicotine is obtained from tobacco plants by extraction or steam distillation. Particularly suitable for this, just as for caffeine, is destraction with supercritical carbon dioxide. [567] Nicotine-rich Mapacho is cultivated for this purpose in the USA but also the waste from tobacco processing is a suitable source. The annual worldwide production for pharmaceutical purposes reaches a total of around 35-40 tonnes, whereof most is attributed to nicotine replacement therapy (nicotine containing patches, nasal spray, chewing gum, lollipops) for smoking cessation. 

Starting material for the synthesis of varenicline is o-bromofluorobenzene, which reacts (via benzyne) with cyclopentadiene in a Diels-Alder reaction. Oxidative ring-opening and reductive amination provides a N-benzylbenz-azepine derivative. After N-protection with trifluoroacetic anhydride, nitration with a mixture of nitric andtrifluoromethanesulfonic acids, reduction, and condensation with glyoxal, hydrolysis of the trifluoroacetamide as a final step provides the active compound in good overall yield. [568, 569] 

Quadbeck-Seger, R. Faust, G. Knaus, A. Maelicke, U. Simeling, Chemie-rekorde, Wiley-VCH, Weinheim, 2nd Edn., 1999,1. 

Kleemann, J. Engel, Pharmaceutical Substances, 3rd Edn., Thieme, Stuttgart, 1999, 310. 

Chevillard, S. Jouquey, F. Bree, M.-N. Mathieu, J. P. Stepniewski, J. P. Tillement, G. Hamon, P. Corvol, /. Cardiovascular Pharm. 23rd Suppl. 4 (1994) SI 1. 

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