3Methyl
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Synthesis of Nicotine and Analogues
I am interested in the synthesis of nicotine and its analogues. I found a study reporting a 52% yield of (S)-(-)-nicotine and (S)-(-)-5-methylnicotine
from the amino acid L-proline. Can someone please find this study for me?
Chavdarian, C. G., Sanders, E. B., & Bassfield, R. L. (1982). Synthesis of optically active nicotinoids. The Journal of Organic Chemistry, 47(6),
1069-1073.
Thanks so much.
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sonogashira
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Attachment: J. Org. Chem., 1982, 47, 06, 1069-1073.pdf (704kB)
This file has been downloaded 1403 times
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Refinery
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Is it possible to make synthetic nicotine with similar effects that of nature?
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DraconicAcid
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Pure nicotine will have the same effect regardless of whether its natural or synthetic. Of course, natural nicotine is never used as the pure
material, and any homemade synthetic stuff is unlikely to be pure, and will have different impurities than the naturally-sourced stuff.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Dr.Bob
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The key feature of nicotine, natural or synthetic, is its toxicity, LD50 of ~40 and 60 milligrams (the total amount in about 2 cigarettes if all of
the nicotine was absorbed) in adults and about 1 mg/kg in children (less than 1 cigarette). So don't leave it near kids. It would be very expensive
to make it synthetically verses extracting it from tobacco leaves, which are still available in NC. Also that article did not make optically pure
nicotine, only partly resolved (-) nicotine, so the synthetic would NOT be the same in that case, as it is not optically pure, which the natural
nicotine is. Plus that route looks painful in terms of chemistry.
But synthetic nicotine analogs are widely used as pesticides, imidacloprid being a good example of one which is more toxic to bugs than humans. Note
that it does not have any chiral centers, thus much easier to make. Thiamethoxam has even more interesting chemistry and is easier to make that it
looks, due to a fortuitous route to the chlorothiazole piece, some of the best process work I have ever seen. Unfortunately that made it easy to make
illegally in China, without patent law enforcement, so it was on the market there before even being approved for use in the US.
Pfizer, Targacept and several other companies have made thousands of nicotine derivatives, looking for useful compounds, much of that work is
published. Chantix and Aricept are but two examples or nicotinic drugs.
Note: "I found a study reporting a 52% yield of (S)-(-)-nicotine and (S)-(-)-5-methylnicotine from the amino acid L-proline." - This method is many
steps and provides about 50-60% yield at each step, for an overall yield of single digits, and an optical purity of only 24%, so this is not a 52%
yield in any way.
Try Google or Google scholar to find lots of this information.
Eg,
Expert Opin Drug Discov. 2007 Sep;2(9):1185-1203.
Nicotinic receptors as targets for therapeutic discovery.
Lippiello P1, Bencherif M, Hauser T, Jordan K, Letchworth S, Mazurov A.
http://www.ncbi.nlm.nih.gov/pubmed/23496128
------------
Curr Top Med Chem. 2004;4(6):609-29.
Recent developments in the synthesis of nicotinic acetylcholine receptor ligands. by Breining SR.
http://www.ncbi.nlm.nih.gov/pubmed/14965298
----------------
Nicotinic receptors as targets for therapeutic discovery
September 2007, Vol. 2, No. 9 , Pages 1185-1203 (doi:10.1517/17460441.2.9.1185)
http://informahealthcare.com/doi/abs/10.1517/17460441.2.9.11...
[Edited on 26-2-2014 by Dr.Bob]
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mr.crow
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Very interesting post, Dr.Bob
I found a paper about Thiamethoxam. They talk about how they developed the structure and synthesis routes. It doesn't say where the 5-member ring comes from though.
Double, double toil and trouble; Fire burn, and caldron bubble
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Dr.Bob
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The chlorothiazole methyl chloride piece comes from (IIRC) a reaction of isoprene, a sulphur source and chlorine source plus something else cheap and
works in about 99% yield. It is in a later patent which I don't have around. But it can be made from all cheap chemicals in high yield. Before
that route it was a much more expensive compound to get. Those compounds are an interesting story; unfortunately, they also appear to be very potent
on bees, which may be contributing to the bee colony collapse problem. Nothing is ever simple. But they are safer than some of the pesticides that
they replace like Chlordane.
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