Methylecgonidine (anhydromethylecgonine; anhydroecgonine methyl ester; AEME) is a chemical intermediate derived from

ecgonine Ecgonine (tropane derivative) is a tropane alkaloid found naturally in coca leaves. It has a close structural relation to cocaine: it is both a metabolite and a precursor, and as such, it is a controlled substance in many jurisdictions, as are ...

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

. Methylecgonidine is a

pyrolysis Pyrolysis is a process involving the Bond cleavage, separation of covalent bonds in organic matter by thermal decomposition within an Chemically inert, inert environment without oxygen. Etymology The word ''pyrolysis'' is coined from the Gree ...

product formed when

crack cocaine Crack cocaine, commonly known simply as crack, and also known as rock, is a free base form of the stimulant cocaine that can be Smoking, smoked. Crack offers a short, intense Euphoria (emotion), high to smokers. The ''Manual of Adolescent Sub ...

is smoked, making this substance a useful biomarker to specifically test for use of crack cocaine, as opposed to powder cocaine which does not form methylecgonidine as a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

. Methylecgonidine has a relatively short half-life of 18–21 minutes, after which it is metabolised to ecgonidine, meaning that the relative concentrations of the two compounds can be used to estimate how recently crack cocaine has been smoked. Methylecgonidine has been shown to be specifically more harmful to the body than other byproducts of cocaine; for example to the heart, lungs & liver. The toxicity is due to a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

effect at M1 and M3 muscarinic receptors, leading to

DNA fragmentation DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually a ...

and neuronal death by

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. AEME is also used in scientific research for the manufacture of

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decade ...

analogues such as troparil, dichloropane, iometopane, and CFT. Methylecgonidine could also theoretically be used to produce

and so may be a

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

in some countries.

Synthesis

Methylecgonidine can be synthesized non pyrolytically from cocaine via

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

followed by

esterification In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

with methanol. Methylecgonidine synthesis 2

The scheme by Kline is based on the reaction of 2,4,6-cycloheptatriene-7-carboxylic acid with methylamine. This is a modified version of by Grundmann and Ottmann. In the accompanying patent these same authors react their methylecgonidine with two equivalents of PhLi to form a tertiary alcohol by "hard" addition to the ester and not "soft"

Michael addition In organic chemistry, the Michael reaction or Michael 1,4 addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a c ...

. However, the product is only one tenth the potency of

atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...

. The methyl 2,4,6-cycloheptatriene-1-carboxylate can be made synthetically. Methylecgonidine synthesis 3

Davies ''et al.'' synthesized (''R''/''S'')-methylecgonidine by a tandem cyclopropanation/ Cope rearrangement. Thus, reaction of methyldiazobutenoate (2) with 5 equiv of ''N''-((2-(TMS)ethoxy)carbonyl)pyrrole (1) in the presence of rhodium(II) hexanoate/hexane gave the .2.1azabicyclic system (''R''/''S'')-8 in 62% yield. The unsubstituted double bond was selectively reduced using Wilkinson catalyst to provide N-protected anhydroecgonine methyl ester ((''R''/''S'')-4). Following deprotection of N8 nitrogen with TBAF and reductive methylation with formaldehyde and sodium cyanoborohydride, (''R''/''S'')-5 was obtained in overall good yield.

References

{{Reflist Tropane alkaloids Cycloalkenes Methyl esters

Synthesis

See also

References