Synthesis Of Varenicline And Route Optimization

In recent decades, the harmfulness of smoking on human health, has attracted widespread attention all over the world. As a result, a variety of smoking cessation medications emerged. Not only could the nicotine in tobacco lead to all kinds of lung diseases, but also had the addictive nature, resulting in less significant effect for most of the traditional smoking cessation drugs. A new smoking cessation drug varenicline developed by the American pharmaceutical giant Pfizer, was approved to entering the market by FDA in 2006. After more than three years of explosive growth, varenicline occupied the dominant position of smoking cessation drugs market. Clinical research shown that varenicline had unique dual-action mechanism (partial agonists and antagonists). Due to stable efficacy, low side effect, high security, varenicline was obviously superior to many conventional smoking cessation drugs.In this thesis, action mechanism and development process of smoking cessation drugs were reviewd, and all kinds of synthetic methods of varenicline reported in the literatures were summarized. On the basis of improving yield, reducing costs, simplifying operations, energy conservation and environmental protection, we designed the following synthetic route.Anthranilic acid as starting material reacted with isoamyl nitrite and cyclopen-tadiene to benzonorbornadiene(1) by diene addition, then 1 was oxidized to 2,3-dihy-dro-1H-inden-1,3-diformaldehyde (2) by the ozone. Then, dialdehyde 2 reacted with benzylamine to 2,3,4,5-tetrahydro-3-benzyl-1,5-methano-lH-3-benzazepine(3), which was reduced to 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine(4), an important intermediate of the target product varenicline. Then,4 was converted to 2,3,4,5-tetrahydro-3-(trifluoroacetyl)-1,5-methano-lH-3-benzazepine(5) by trifluoro-acetyla-tion, then 5 was substituted to 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl)-1,5-methano-lH-3-benzazepine (6), which was reduced to 2,3,4,5-tetrahydro-3-(trifluoro-acetyl)-1,5-methano-1H-3-benzazepine-7,8-diamine(7),then 7 reacted with glyoxal to 2,2,2-trifluoro-1-(6,7,9,10-tetrahydro-6,10-methano-8H-pyrazino[2,3-h][3] benzaz-epin-8-yl) ethanone (8). Finally,8 was deprotected to the target product varenicline.Reaction conditions and treatment processes in each step of synthetic route were optimized, and the overall yield was increased by 8.7%(from 12.7% to 21.4%), in addition, the synthetic process had the advantages of low cost, energy saving and simple operation, which laid a good foundation for industrial production of varenicline. Structures of the target product and all intermediates were confirmed by 1HNMR and GC-MS.