5/28/2018 Synthesis of Cocaine Analogs From Arecoline

1/3

Synthesis of Cocaine analogs from Arecoline

Written by Beagle, edited by Rhodium

[ Back to the Chemistry Archive ]

Introduction

This is one of the most promising area of research on cocaine analogs that !ve come across"n the article [1], the authors #ere attempting to come up #ith an e$uivalent of methadone forcocaine addicts" That is, a substance that #ould have some of the effects of cocaine #ithoutall the euphoria %Coke&'ite(, guess it #ill be called)" The research #as based on some #orkdone in *+- %by Clarke [2]) in #hich a series of similar compounds #as made and found notto cause stimulation in mice %i"e" no fun)" .o#ever, in this study, the compounds #ere foundto be up to -/ times the potency of cocaine in blocking dopamine transport or binding ofcocaine to its receptor" 0o the results are rather confusing" 1ossibly the researchers haveactually found a lead in their search for coke&adone, or maybe they have found a series ofridiculously easy to synthesi2e highly potent coke analogs" 3ither #ay, interesting #ork"Currently they are shooting up monkeys to see if they like it or not, but it may be years beforethey publish their #ork" 4aybe someone out there could help them out" al#ays say, neversend a monkey to do a man!s #ork"

n Clarke!s *+- paper [2], a series of structurally reduced cocaine analogs are synthesi2ed in#hich 5 carbons and an ester group have been removed from the tropane skeleton, giving 6&

phenyl&piperidines #ith an ester group at the -&position" The most active compound in theirseries is about -/ times the potency of cocaine %in blocking dopamine uptake)" The synthesis

is much easier than any other active cocaine analog, and starts from non&e7otic reagents"

The main starting material used by the authors is Arecoline %-,6&unsaturated 8&methyl&piperidine&-&carbo7ylic acid methyl ester), the active principle of the popular red betel nut"Treatment of this alpha, beta&unsaturated ester #ith the 9rignard reagent 6Chlorophenylmagnesium Bromide gave rise to four products, easily grouped into t#o racemicforms of each cis& and trans& isomer" The racemic cis&isomer is t#ice as potent as cocaine,#hile the racemic trans&isomer is only half as strong"

The authors start #ith arecoline %the active compound in betel nut: 8&methyl&piperidine& -&carbo7ylic acid methyl ester #ith a double bond bet#een the - and 6 positions)" Reaction of

this #ith a 6&chlorophenylmagnesium bromide grignard reagent gives a mi7ture of a total offour discrete entities: A cis& and trans&mi7ture in a -:* ratio, each constisting of a of t#oisomers, each isomer also being racemic, all #hich the #hich the authors resolve throughfractional crystalli2ation as their diben2oyl tartaric acids, but this is not strictly necessarysince each of the isomers are active" Arecoline .ydrobromide is a fairly cheap commercialstarting material, ;/g from Aldrich" Also, think that it is used in veterinary medicine"

Synthetic Outline

http://www.erowid.org/archive/rhodium/chemistry/index.htmlhttp://www.erowid.org/archive/rhodium/chemistry/index.html

5/28/2018 Synthesis of Cocaine Analogs From Arecoline

2/3

The Arecoline freebase #as prepared by treating the Arecoline .ydrobromide of commerce#ith concentrated a$ueous sodium bicarbonate, follo#ed by e7traction #ith methylenechloride, thorough drying of the e7tracts over anhydrous 4agnesium 0ulfate, follo#ed bysuction filtration and evaporation of the solvent in vacuo" The freebase #as then used as is inthe ne7t step"

To a solution of *??ml of *4 6&chlorophenylmagnesium bromide in //ml ether #as added*5"+g of arecoline freebase in -//ml ether at &*/@C" The mi7 #as stirred at &*/@C for -/ min,

poured onto ice and treated #ith 5//ml of */ .Cl" The a$ueous layer #as separated,#ashed #ith 5//ml ether, cooled in an ice bath, and *//ml of saturated sodium bicarb"solution added" The solution #as e7tracted #ith 57*//ml of ether, #ashed #ith brine, dried,and concentrated in vacuo" The crude mi7ture #as crystalli2ed from 3tAc=he7ane to giveracemic cis&isomer as a #hite solid %>g, 55)" Additional cis&isomer %Total: *5"6g, >?, mp+

5/28/2018 Synthesis of Cocaine Analogs From Arecoline

3/3