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             Structurally simple cocaine analogs (Posted by Beagle)
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This is one of the most promising area of research on cocaine analogs that I've
come across. In the following ref, the authors were attempting to come up with
an equivalent of methadone for cocaine addicts. That is, a substance that would
have some of the effects of cocaine without all the euphoria (Coke-Lite®, I
guess it will be called). The research was based on some work done in ’73 (by
Clarke) in which a series of similar compounds was made and found not to cause
stimulation in mice (i.e. no fun). However, in this study, the compounds were
found to be up to 30 times the potency of cocaine in blocking dopamine transport
or binding of cocaine to its receptor. So the results are rather confusing.
Possibly the researchers have actually found a lead in their search for
coke-adone, or maybe they have found a series of ridiculously easy to synthesize
highly potent coke analogs. Either way, interesting work. Currently they are
shooting up monkeys to see if they like it or not, but it may be years before
they publish their work. Maybe someone out there could help them out. I always
say, never send a monkey to do a man's work.

         Journal of Medicinal Chemistry, Vol 41, No 11, p 1962-9 (1998)

    Chemistry and pharmacology of the piperidine-based analogues of cocaine.
     Identification of potent DAT inhibitors lacking the tropane skeleton.

In this paper, a series of structurally reduced cocaine analogs are synthesized
in which 2 carbons and an ester group have been removed from the tropane
skeleton, giving 4-phenyl-piperidines with an ester group at the 3-position.
The most active compound in their series is about 30 times the potency of
cocaine (in blocking dopamine uptake). The synthesis is much easier than any
other active cocaine analog, and starts from non-exotic reagents.

The authors start with arecoline (the active compound in betel nut:
N-methyl-piperidine-3-carboxylic acid methyl ester with a double bond between
the 3 and 4 positions). Reaction of this with 4-chlorophenyl magnesium bromide
gives the final compound. This synthesis yields a mixture of isomers, which the
authors resolve with dibenzoyl tartaric acids, but this is not strictly
necessary since each of the isomers are active. Arecoline is a fairly cheap
starting material, $80/50g from Aldrich. Also, I think that it is used in
veterinary medicine.

So here is the outline of the synthesis:

To a solution of 166ml of 1M 4-chlorophenylmagnesium bromine in 700ml ether was
added 12.9g of arecoline freebase in 300ml ether at -10 C. The mix was stirred
at -10 C for 30 min, poured onto ice and treated with 200ml of 10% HCl. The
aqueous layer was separated, washed with 200ml ether, cooled in an ice bath, and
100ml of saturated sodium bicarb. solution added. The solution was extracted
with 2x100ml of ether, washed with brine, dried, and concentrated in vacuo. The
crude mixture was crystallized from EtOAc/hexane to give racemic cis-isomer as a
white solid (5g, 22%). Additional product, as well as the trans isomer was
obtained by flash chromatography of the mother liquor.

Alternatively, it looks like that 4-piperidone that you fentanyl-heads have been
dreaming about could also be used to synthesize these compounds. I picture
reaction of 4-piperidone with e.g. methyl chloroformate to give piperidone
3-methylcarboxylate (hey drone: enolate chemistry!). This could then be reduced
to the alcohol, and dehydrated to give arecoline. Or the piperidone
3-methylcarboxylate could be reacted with phenylmagnesium bromide, dehydrated,
and reduced to give the final compound. Note the use of one precursor to make
both highly potent opiate and cocaine analogs. Talk about speedballs!

Or what about starting from nicotinic acid (pyridine-3-carboxylate; a
B-vitamin)? That should be cheap as dirt. Seems to me that reaction with
phenyllithium would give  4-phenyl-3-carboxyl-tetrahydropyridine, which would
only need esterification and reduction to give the final compound. Or maybe
there would be a better way to start from nicotinic acid?

In the last two proposed syntheses, care would need to be taken to avoid
formation of a potentially nerotoxic MPTP analog!

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