Methylecgonidine: Difference between revisions

{{Redirects|AEME|the Australian Army corps |Royal Australian Electrical and Mechanical Engineers}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 442064699

| ImageSize = 200px

| IUPACName = Methyl trop-2-ene-2β-carboxylate

| SystematicName = Methyl (1''R'',5''S'')-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate

|Section1={{Chembox Identifiers

| InChI = 1/C10H15NO2/c1-11-7-3-5-8(10(12)13-2)9(11)6-4-7/h5,7,9H,3-4,6H2,1-2H3/t7-,9+/m0/s1

| CASNo_Ref = {{cascite|correct|??}}

| PubChem = 119478

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| SMILES = CN2[C@@H]/1CC[C@@H]2C\C=C\1C(=O)OC

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 58C337KP3E

|Section2={{Chembox Properties

| C=10|H=15|N=1|O=2

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

'''Methylecgonidine''' (anhydromethylecgonine; anhydroecgonine methyl ester; AEME) is a chemical intermediate derived from [[ecgonine]] or [[cocaine]].

Methylecgonidine is a [[pyrolysis]] product formed when [[crack cocaine]] 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]].<ref>{{cite journal | vauthors = Scheidweiler KB, Plessinger MA, Shojaie J, Wood RW, Kwong TC | title = Pharmacokinetics and pharmacodynamics of methylecgonidine, a crack cocaine pyrolyzate | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 307 | issue = 3 | pages = 1179–87 | date = December 2003 | pmid = 14561847 | doi = 10.1124/jpet.103.055434 | s2cid = 15619796 }}</ref> 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,<ref>[http://jpet.aspetjournals.org/cgi/content/full/307/3/1179/FIG6 Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate - Scheidweiler et al. 307 (3): 1179 Figure IG6 - Journal of Pharmacology and Experimental Therapeutics<!-- Bot generated title -->]</ref> lungs<ref name="pmid11159694">{{cite journal | vauthors = Yang Y, Ke Q, Cai J, Xiao YF, Morgan JP | title = Evidence for cocaine and methylecgonidine stimulation of M(2) muscarinic receptors in cultured human embryonic lung cells | journal = British Journal of Pharmacology | volume = 132 | issue = 2 | pages = 451–60 | date = January 2001 | pmid = 11159694 | pmc = 1572570 | doi = 10.1038/sj.bjp.0703819 }}</ref> & liver.<ref name="pmid12482236">{{cite journal | vauthors = Fandiño AS, Toennes SW, Kauert GF | title = Studies on hydrolytic and oxidative metabolic pathways of anhydroecgonine methyl ester (methylecgonidine) using microsomal preparations from rat organs | journal = Chemical Research in Toxicology | volume = 15 | issue = 12 | pages = 1543–8 | date = December 2002 | pmid = 12482236 | doi = 10.1021/tx0255828 }}</ref> The toxicity is due to a [[partial agonist]] effect at [[Muscarinic acetylcholine receptor M1|M1]] and [[Muscarinic acetylcholine receptor M3|M3 muscarinic receptors]], leading to [[DNA fragmentation]] and neuronal death by [[apoptosis]].<ref>{{cite journal | vauthors = Garcia RC, Dati LM, Torres LH, da Silva MA, Udo MS, Abdalla FM, da Costa JL, Gorjão R, Afeche SC, Yonamine M, Niswender CM, Conn PJ, Camarini R, Sandoval MR, Marcourakis T | display-authors = 6 | title = M1 and M3 muscarinic receptors may play a role in the neurotoxicity of anhydroecgonine methyl ester, a cocaine pyrolysis product | journal = Scientific Reports | volume = 5 | pages = 17555 | date = December 2015 | pmid = 26626425 | pmc = 4667193 | doi = 10.1038/srep17555 | bibcode = 2015NatSR...517555G }}</ref>

AEME is also used in scientific research for the manufacture of [[phenyltropane]] [[analog (chemistry)|analogues]] such as [[troparil]], [[dichloropane]], [[iometopane]], and [[(-)-2β-Carbomethoxy-3β-(4-fluorophenyl)tropane|CFT]]. Methylecgonidine could also theoretically be used to produce [[cocaine]] and so may be a [[controlled substance]] in some countries.

==Synthesis==

[[File:Methylecgonidine synthesis 1.svg|thumb|left|400px|Methylecgonidine synthesis from cocaine]]{{clear left}}

Methylecgonidine can be synthesized non [[pyrolysis|pyrolytically]] from cocaine via [[hydrolysis]]/[[dehydration]]<ref>{{cite journal | vauthors = Basmadjian GP, Singh S, Sastrodjojo B, Smith BT, Avor KS, Chang F, Mills SL, Seale TW | display-authors = 6 | title = Generation of polyclonal catalytic antibodies against cocaine using transition state analogs of cocaine conjugated to diphtheria toxoid | journal = Chemical & Pharmaceutical Bulletin | volume = 43 | issue = 11 | pages = 1902–11 | date = November 1995 | pmid = 8575031 | doi = 10.1021/ja01502a049 }}</ref> followed by [[esterification]] with methanol.<ref>{{cite journal | vauthors = De Jong AW | title = Some properties of the ecgonines and their esters II. The structural formulae of the ecgonines and ecgonidine. | journal = Recueil des Travaux Chimiques des Pays-Bas | date = 1937 | volume = 56 | issue = 2 | pages = 186–97, 198–201 | doi = 10.1002/recl.19370560215 }}</ref><ref>{{cite journal | vauthors = Matchett JR, Levine J | year = 1941 | title = Isolation of Ecgonidine Methyl Ester from Coca Seeds 1| journal = J. Am. Chem. Soc. | volume = 63 | issue = 9| pages = 2444–2446 | doi=10.1021/ja01854a038}}</ref>

[[File:Methylecgonidine synthesis 2.svg|thumb|left|500px|Methylecgonidine synthesis by Kline]]{{clear left}}

The scheme by Kline<ref>{{cite journal | vauthors = Kline RH, Wright J, Fox KM, Eldefrawi ME | title = Synthesis of 3-arylecgonine analogues as inhibitors of cocaine binding and dopamine uptake | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 7 | pages = 2024–7 | date = July 1990 | pmid = 2362282 | doi = 10.1021/jm00169a036 }}</ref> is based on the reaction of 2,4,6-cycloheptatriene-7-carboxylic acid with methylamine. This is a modified version of {{US patent|2783235}} by Grundmann and Ottmann. In the accompanying patent {{US patent|2783236}} these same authors react their methylecgonidine with two equivalents of [[phenyllithium|PhLi]] to form a tertiary alcohol by "hard" addition to the ester and not "soft" [[Michael addition]]. However, the product is only one tenth the potency of [[atropine]]. The methyl 2,4,6-cycloheptatriene-1-carboxylate can be made synthetically.<ref>{{Cite web|url=http://www.chemsynthesis.com/base/chemical-structure-15475.html|title=Methyl 2,4,6-cycloheptatriene-1-carboxylate - C9H10O2, density, melting point, boiling point, structural formula, synthesis}}</ref><ref>{{cite journal | vauthors = Anciaux AJ, Demonceau A, Noels AF, Hubert AJ, Warin R, Teyssie P |doi=10.1021/jo00318a010|title=Transition-metal-catalyzed reactions of diazo compounds. 2. Addition to aromatic molecules: Catalysis of Buchner's synthesis of cycloheptatrienes|journal=The Journal of Organic Chemistry|volume=46|issue=5|pages=873–876|year=1981 |hdl=2268/237697 |url=https://orbi.uliege.be/handle/2268/237697}}</ref>

[[File:Methylecgonidine synthesis 3.svg|thumb|center|700px|Methylecgonidine synthesis by [[Huw Davies (chemist)|Davies]]. [[Enantioselective]]<ref name="DaviesHuby1992">{{cite journal| vauthors = Davies HM, Huby NJ |title=Enantioselective synthesis of tropanes by reaction of rhodium-stabilized vinylcarbenoids with pyrroles|journal=Tetrahedron Letters|volume=33|issue=46|year=1992|pages=6935–6938|issn=0040-4039|doi=10.1016/S0040-4039(00)60899-7}}</ref>]]

Davies ''et al.'' synthesized (''R''/''S'')-methylecgonidine by a tandem cyclopropanation/[[Cope rearrangement]].<ref>{{cite journal | last1 = Davies | first1 = H. M. L. | last2 = Saikali | first2 = E. | last3 = Young | first3 = W. B. | year = 1991 | title = Synthesis of (.+-.)-ferruginine and (.+-.)-anhydroecgonine methyl-ester by a tandem cyclopropanation/Cope rearrangement| journal = J. Org. Chem. | volume = 56 | issue = 19| pages = 5696–5700 | doi=10.1021/jo00019a044}}</ref><ref>{{cite journal | vauthors = Davies HM, Young WB, Smith HD | title = Novel entry to the tropane system by reaction of rhodium (II) acetate stabilized vinylcarbenoids with pyrroles. | journal = Tetrahedron Letters | date = January 1989 | volume = 30 | issue = 35 | pages = 4653–6 | doi = 10.1016/S0040-4039(01)80766-8 }}</ref> 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 [3.2.1]-azabicyclic 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.

== See also ==

* [[Arecoline]]

* [[Anatoxin-a]]

* [[Tropacocaine]]

{{Reflist}}

[[Category:Tropane alkaloids]]

[[Category:Cycloalkenes]]

[[Category:Methyl esters]]