Minggu, 07 Oktober 2012

Cocaine


Properties and History
The coca plant, Erythroxylon coca
Cocaine is an alkaloid found in the leaves of the small tree Erythroxylon coca, which is native to the tropical mountains of Peru, Bolivia and Colombia. Indians in this area place in the cheek a mixture of coca leaves and basic material like ground seashell or ashes, so that the saliva extracts the free base that is ingested. Consumers of the drug are easily spotted by their hump in the cheek. There is evidence of very ancient consumption of coca leaves. Ceramics depicting human figures with a cheek bulge were found in archaeological sites from Peru, dated from1900-1750B.C. Remains of coca leaves were encountered in 2000 years-old mummies from Nazca in Peru.
As the content of cocaine in dry coca leaves is only 0.4-0.8%, it is very doubtful that its traditional ingestion causes any serious threat for the health, producing a damage akin to moderate tobacco smoking.
The Incas consumed coca leaves for religious and ceremonial purposes. In1533, the Incas were conquered by the troops of the Spanish conquistador Pizarro. A few years later in 1551, the Bishop of Cuzco prohibited the cultivation and consumption of coca, and its possession was punished by death. Coca ingestion was viewed as an obstacle for the conversion of the Indians into Christianity, for it was a tie with their past religion. Nevertheless, later it was found that coca increased the stamina of Indian laborers and in 1569 King Philip IIdecreed that coca was not devilish.
As the long journey by ship to Spaincaused coca leaves to deteriorate, theeffects of coca ingestion were notexperienced in Europe for a long time.
Following the isolation of pure cocaineform coca leaves in 1862 (2), the puredrug became available in Europe from theMerck Company. At the same time cocaextracts began to be added to beveragesthat were sold as tonics. One of the mostpopular was the so-called Mariani´s CocaWine, which was advertised as a drink able to lift spirits and alleviate fatigue. Theoriginal recipe for the preparation of Coca-Cola, which was invented in 1886 as a“tonic” medicine by John Pemberton,included an extract of coca leaves, andsugar was added to abate the bitternessof cocaine. By 1903 the alkaloid wasremoved and substituted for caffeine inorder to keep the tonic properties of theliquor.
In these early days of candid use of cocaine, this drug was considered ahealthful medicine that helped to abatedepression; a many distinguishedscientists endorsed its use. One notableinstance was Sigmund Freud (3), thefather of Psychoanalysis. He tried the drugon himself and even wrote a book called“On Cocaine” in which he praises itsconsumption and gives very detailedaccounts over the effect of the drug onhimself. Thus, he wrote for example“During this first trial I experienced a shortperiod of toxic effects, which did not recurin subsequent experiments. Breathingbecame slower and deeper and I felt tiredand sleepy; I yawned frequently and feltsomewhat dull. After a few minutes theactual cocaine euphoria began, introducedby repeated cooling eructation.” Herecommended cocaine to one of hispatients who were suffering frommorphine addiction. His enthusiasm for the drug was later completely removed when he observed the increasing doses needed by this patient, and the on set of full-fledged cocaine psychoses including “white snakes creeping over his skin.” In fact, this is an example of “formication,” a hallucination commonly experienced by cocaine abusers, consisting in feeling ants, insects, spiders, or– as in this case– snakes, crawling over or under the skin.
Beginning at 1890, a growing number of scientific evidences showed the highly addictive nature of cocaine consumption and by 1914, the possession or sale of cocaine was prohibited in the United States, with the exception of medical uses.
Cocaine is a white powder with bitter taste that produces stimulation of the central nervous system, due to blockage of reuptake of domanine (4). This is followed by depression, and as the timing of the on set of the depression phase varies depending on the area of the nervous system, a mixed effect of stimulation and depression can be simultaneously observed (5). Another effect of cocaine is local anaesthesia and it was used in surgery– mainly in the eye–until drugs with less addictive properties became available. Interestingly, most of the cocaine substitutes for surgery have share several structural features with cocaine, and normally consist in amino alcohol benzoates or p –aminobenzoates(1).
Following the prohibition of non-medical consumption of cocaine at the beginning of the twentieth century, the number of addicts was drastically reduced, as the black market for the drug was quite small. By the end of the 1960s, the illegal extraction of pure cocaine from Erythroxylon coca leaves began to be extensive in South American countries where this plant is native. This marked the beginning of massive illegal trafficking of cocaine to the United States and Europe, causing a second and more intense period of cocaine abuse reaching epidemic levels after half a century of very small consumption. One wonders why the illegal extraction of cocaine from natural sources became prevalent as late as one century after pure cocaine was first isolated. Nowadays, there are about 2.1 million cocaine consumers in the United States, from who about 600,000 are severely addicted.

ISOLATION AND STRUCTURALELUCIDATION
Pure l -cocaine was isolated from coca leaves for the first time by Wöhlerin 1862. It was characterized as an alkaloid with the formula C17H21O4N. The total synthesis of cocaine by Willstäter in 1923  closed a long chapter of degradative and structural research and allowed the determination of the right atom connectivity of the alkaloid, which was depicted with formula 1.
The molecule contains four asymmetric carbons and thus eight diastereomeric isomers are possible, from which four can be discarded because of geometric constraints. Stephen Findlay and Gábor Fodor established the relative stereochemistry in the 1950´s, by a close examination of the degradative cocaine chemistry and taking advantage of incisive mechanistic considerations. It was then established that cocaine consists in2β-carbomethoxy-3β-benzoyloxytropane.

Figure 1
 

Figure 2
 



Finally, the absolute stereochemistry of natural l -cocaine was proved to be as portrayed in Figure1 by Hardegger and Ottin 1955. They showed that hydrolysis of the esters in l -cocaine, followed bychromic acid oxidation yields the same acid 3, that could be obtained from L(+)-glutamic acid (Figure2).

SYNTHESIS
1923: Willstäter´s Preparation. Regardless of unknown absolute and relative stereochemistry, the first total synthesis of cocaine is an enantioselective one.
Cocaine was first prepared in 1923 byWillstäter et al. This synthesis is veryremarkable because, although at this timeboth the relative and the absolutestereochemistry of cocaine were unknown,they were able to prepare this alkaloid inoptically active form.
 
Condensation of butanedial [4]withmethylamine andmonomethylacetonedicarboxylate5yielded methyltropinone-2-carboxylate [6].Reduction of tropinone6withsodium amalgamproduced a mixtureof ecgoninemethylester [7] andpseudoecgoninemethyl ester[8].
The mixture of esters7and8was benzoylated withbenzoyl anhydride, resulting in a mixture of cocaine [2] and pseudococaine [9], whichwas separated by fractional crystallization.The more soluble benzoate wasdl -cocaine.Finally,dl -cocaine was resolved via thecorresponding tartrate. Thus, crystallizationwith  l  -tartaric acid yielded thed -cocainel -bitartrate, whose free base is naturald -cocaine.

1958: Preobrazhenskii´s Preparation.Some improvements on Willstäter´ssynthesis are made.
This Russian group retook Willstäter´ssynthesis and introduced some improvements, like the in situGeneration of the unstable butandial by acidic hydrolysis of dimethoxyetrahydrofuran 11. Thus, treatment of furane with bromine in methanol leads to dimethoxydihydrofurane 10 that is hydrogenated to intermediate 11. Dimethoxytetrahydrofurane 11 is treated with HCl, and the resulting butandial is condensed with the dipotassium salt of acetonedicarboxylic acid monomethyl ester and methylamine, resulting in 47% yield of methyl tropanonecarboxylate 6.This is converted to dl -cocaine, following Willstäter´s procedure, by reduction to ecgonine methyl ester 7with sodium amalgam, followed by benzoylation with benzoyl chloride.

 

1978: Tufariellos´s Preparation.An intramolecularnitronecycloaddition as the key step for thefirst stereoselective synthesis of cocaine.
The previous syntheses, which are based on the intermediacy of methyl tropanone carboxylate 6,have serious stereochemical problems. The ester group in compound 6 so easily epimerized that, for practical matters, it is not relevant which epimer is used for the next carbonyl reduction, as there would be a very quick equilibration before formation of the alcohol 7. On the other hand, it is very difficult to perform a stereoselective reduction of the ketone in 6, leading to the desired equatorial alcohol 7. Not surprisingly, the reduction of tropinone 6 to ecgoninemethylester [7], which contains an unstable axial ester, gives a mixture of diastereomers, from which compound 7 is isolated in lowyield.
 
Tufariello´s elegant preparation of cocaine (11) addresses the stereochemical problem by means of a highly stereo selective intramolecularcycloaddition of a nitrone on a trans-olefin. The preparation begins with the pyrroline oxide 12 that is reacted with methyl 3-butenoate 13, leading to adduct 14. Oxidation of compound 14 with m -chloroperbenzoicacid produces alcohol 15. As attempteddehydration of alcohol 15 gave low yields due to interference of the nitronemoiety, it was necessary to protect the nitrone as an adduct by heating with methyl acrylate. Theresulting adduct16could be efficientlydehydrated by treatment with mesylchloride, followed by base. In the keyreaction, heating of adduct in refluxing xylene led to a retro-addition of methylacrylate, resulting in the formation of thenitrone intermediate18that cyclizesin situto compound19. Thetransstereochemistry in the olefin inintermediate18dictates the desiredconfiguration on the ester in compound19.
The rest of the synthesis follows a moreordinary chemistry, beginning withN-methylation to the salt
20that is reducedto ecgonine methyl ester7with zinc inacetic acid. Finally, compound7 istransformed indl -cocaine followinga known procedure.

1987: Carroll´s Preparation.A re-examination of theprevious syntheses leads to animproved version of theoriginal Willstäter´spreparation as the proposedmethod of choice.
These researchers predeterminedthe goal of studying the bestpractical preparation of opticallyactive cocaine, regardless of scientificnovelty. After judging Tufariello´spreparation as too long, they concentratedin improving the original Willstäter´ssynthesis. In fact, the commercial availabilityof 3-tropanone21allowed an easy entryinto methyl tropanonecarboxylate6 thatcould be converted by known means intococaine (12). Regardless of ineffectivestereocontrol, this route permits thepreparation of cocaine from a readilyavailable commercial compound in only four steps.
Treatment of 3-tropanone21 withdimethyl carbonate and sodium hydrideyields methyl tropinonecarboxylate6 thatcan be resolved in 34% yield via thecorresponding bitartrate. Thereafter,optically active compound6 wastransformed intod -cocaine by standardreduction with sodium amalgam, followedby benzoylation. Interestingly, althoughother more modern reducing agents weretried for the transformation of methyltropinonecarboxylate6into ecgonine methyl ester7, none was as effective asthe sodium amalgam originally used forWillstäter in 1923.
Although Carroll et al preparedunnaturald -cocaine; the procedure isequally suitable for the preparation of naturall -cocaine.

2000: Cha´s Preparation.The enantioselectivedeprotonation of a meso ketone leads to a highly effective stereoselective synthesis of cocaine.
Cha´s synthesis is an outcome of thecurrent alertness paid to the developmentof new enantioselective syntheticprocedures (14). The startingmaterial is the symmetric tropanone49,which is readily accessible andcommercially available. Enantioselectivedeprotonation of tropanone49with chirallithium (R, R)-bis(1-phenylethyl) amide[50] gives a chiral enolate that is reactedwith aldehyde51. This results in a highlystereoselective reaction with an approachfrom the less-hindered exo-face of tropanone49, leading to compound52In90-92%ee.
 
Silylation of alcohol52with TIPSOTf yields ketone53that is reduced underBirch conditions to the thermodynamiccyclohexanol54. After benzoylation of compound54to compound55 withbenzoyl chloride, desilylation withhydrofluoric acid, followed with glycolcleavage with RuCl3and NaIO4, andmethylation of the resulting carboxylic acidwith trimethylsilyldiazomethane yieldedunnaturald -cocaine [22]. Obviously, naturall -cocaine [2] could have been obtained,should the enantiomer of base50beenused. According to the authors “Inasmuchas natural (–)-cocaine is an illicit drug, wedecided to prepare the unnaturalenantiomer.”
How Does Cocaine Affect the Brain?
Cocaine is a strong central nervous system stimulant that increases levels of dopamine, a brain chemical (or neurotransmitter) associated with pleasure and movement, in the brain’s reward circuit. Certain brain cells, or neurons, use dopamine to communicate. Normally, dopamine is released by a neuron in response to a pleasurable signal (e.g., the smell of good food), and then recycled back into the cell that released it, thus shutting off the signal between neurons. Cocaine acts by preventing the dopamine from being recycled, causing excessive amounts of the neurotransmitter to build up, amplifying the message to and response of the receiving neuron, and ultimately disrupting normal communication. It is this excess of dopamine that is responsible for cocaine’s euphoric effects. With repeated use, cocaine can cause long-term changes in the brain’s reward system and in other brain systems as well, which may eventually lead to addiction. With repeated use, tolerance to the cocaine high also often develops. Many cocaine abusers report that they seek but fail to achieve as much pleasure as they did from their first exposure. Some users will increase their dose in an attempt to intensify and prolong the euphoria, but this can also increase the risk of adverse psychological or physiological effects.
What Adverse Effects Does Cocaine Have on Health?
Abusing cocaine has a variety of adverse effects on the body. For example, cocaine constricts blood vessels, dilates pupils, and increases body temperature, heart rate, and blood pressure. It can also cause headaches and gastrointestinal complications such as abdominal pain and nausea. Because cocaine tends to decrease appetite, chronic users can become malnourished as well.
Different methods of taking cocaine can produce different adverse effects. Regular intranasal use (snorting) of cocaine, for example, can lead to loss of the sense of smell; nosebleeds; problems with swallowing; hoarseness; and a chronically runny nose. Ingesting cocaine can cause severe bowel gangrene as a result of reduced blood flow. Injecting cocaine can bring about severe allergic reactions and increased risk for contracting HIV/AIDS and other blood-borne diseases. Binge-patterned cocaine use may lead to irritability, restlessness, and anxiety. Cocaine abusers can also experience severe paranoia—a temporary state of full-blown paranoid psychosis—in which they lose touch with reality and experience auditory hallucinations.
Regardless of the route or frequency of use, cocaine abusers can experience acute cardiovascular or cerebrovascular emergencies, such as a heart attack or stroke, which may cause sudden death. Cocaine-related deaths are often a result of cardiac arrest or seizure followed by respiratory arrest.

9 komentar:

  1. In synthesizing cocaine there will be produced both l-cocaine and d-cocaine, but they both are different in way of producing. L-cocaine is produced naturally while d-cocaine is produced unnaturally. Why do so ? Which one is addictive ?Why ?

    BalasHapus
  2. i will try answer your problem,

    like most organic compounds, has many "isomers." Isomers are two or more compounds which have the same molecular formula but different molecular structures. The variations in structure may give rise to different chemical characteristics. Medina testified that he had not tested the substance to determine whether it consisted of the "levo" isomer of cocaine (l-cocaine) or the "dextro" isomer (d-cocaine). L-cocaine is "natural" cocaine, a drug derived from the coca leaf, whereas d-cocaine is a chemically synthesized compound.

    BalasHapus
  3. I’ve read from some articles about cocain but none of them told the specification of wether d-cocain or l-cocain is addictive. There’s only explanation about how they produced (natural/unnatural) like you asked before. In one of the articles I’ve read there’s only said that a scientist named Shapiro testified that d-cocaine is not the chemical equivalent to l-cocaine and that d-cocaine would have a different physiological effect on the human body than l-cocaine. Prior to this testimony, Medina had also discussed the properties of the two isomers, stating that they "would behave chemically equivalent (sic) . . . except for the rotation of the polarized light . . . in the polarimeter." Thus, both witnesses indicated that there were some differences between the two isomers, although there was an apparent conflict as to whether there was a chemical equivalency.

    Is there any test to distinguish the existence of d-cocain and l-cocain ?

    BalasHapus
  4. An infra-red spectrophotometry spectrum obtained from the precipitate differentiates between l- and d-cocaine. The characteristic crystal habits of the cocaine tartrates themselves are the basis of another suggested crystal test.
    Bowen and Purdie report that identification of the enantiomer and quantification of cocaine can be accomplished by use of circular dichroism spectropolarimetry. Identification of the enantiomer is done by complexing cocaine with an optically active sugar derivative, inducing a structural dissymmetry in the drug molecule. Cocaine concentration is determined by measuring the ellipticity of the cocaine solution and comparing the result with a standard plot. For this procedure to provide accurate results, cocaine must be optically pure and free from optically active contaminants.
    A method for enantiomer identification has been developed that involves adding pure l-cocaine to cocaine recovered from a developed thin-layer chromatography plate and measuring the melting point of the mixture. If the material removed from the plate was not l-cocaine, the mixed melting point will differ from the melting point of l-cocaine alone. Another thin-layer chromatography procedure for identifying cocaine enantiomers consists of hydrolyzing the sample to ecgonine, then re-esterifying with optically pure 2-octanol. The octanyl esters of ecgonine formed from l- and d-cocaine are diastereoisomeric and can be resolved chromatographically.

    BalasHapus
  5. here is one more test to distinguish d-cocain and l-cocain...
    A procedure has been described for the simultaneous identification of cocaine and enantiomer determination by proton magnetic resonance spectrometry. A spectrum of cocaine dissolved in an optically active solvent is obtained by proton magnetic resonance spectrometry. Inter-molecular forces between cocaine and the solvent will shift the resonance peaks of cocaine in a manner that can be used to identify the enantiomer present in the sample.

    BalasHapus
  6. how the mecanisms cocaine affects the brain ?

    BalasHapus
    Balasan
    1. Ok chitra I will try to answer

      In brain cells there are a variety yangdisebut neurotransmitter chemicals. These chemicals work in a single nerve cell connections with other nerve cells (synapses). Some neurotransmitters that are similar to some types of drugs. Semuazat psychoactive (narcotics, psychotropic and other addictive substances) can change behaviors, feelings and thoughts of a person through their effects on one or more neurotransmitters. Neurotransmitters are most responsible for the occurrence of dependence is dopamine (Drug Drugs such as Home Formula No. 2 work on the pineal gland, Medicinal Drugs, HF 4 works on the hypothalamus gland, Medicinal Drugs, HF 5 working Limbic gland in the brain to normalize the nervous system and mood) . portion of the brain is responsible for feelings of life is a system limbus. Hipotalamusadalah part of the limbic system, the center of pleasure. If the drug enters the body, by being swallowed, inhaled, or injected, the drugs alter the composition of the system biokimiawineurotransmitter limbus. Because no drug intake from outside, production tubuhterhenti or disturbed, so he will always need drugs of dependence luar.Yang happen is sort of learning on brain cells

      Hapus
  7. Balasan
    1. Cocaine can be extracted from the leaves with almost any organic solvent. Moisten the dried, powdered leaves with Na carbonate solution and extract with cold benzene or petroleum ether. Extract the organic solution with small amounts of dilute sulfuric acid and basify the extract with Na carbonate (the alkaloids precipitate). Dissolve the precipitate in ether, separate the ether from the aqueous Na carbonate and dry and evaporate in vacuum the ether. Dissolve the residue in methanol and heat with sulfuric acid or methanol HCl; dilute with water and extract with CHCl3. Concentrate and neutralize the aqueous layer and cool to precipitate methylecgonine sulfate, which is converted to cocaine in one step. The alkaloids can also be extracted directly from the powder with dilute sulfuric acid.

      Hapus