Cocaine preparations

The following summary of cocaine preparation and trade was prepared by the California State Attorney General in 1973.)... 

Cocaine is no stranger to us. We are very much aware of the abuse of this once helpful drug and the dangers not only to the psyche but also to the very existence of a body. The following is a chemical explanation of some of the features of cocaine preparation and use. 

Other uses include use as a reaction and extraction solvent in pharmaceutical production as an intermediate for the preparation of catalysts, antioxidants (qv), and perfumes and as a feedstock in the production of methyl isopropenyl ketone, 2,3-butanedione, and methyl ethyl ketone peroxide. Concern has also arisen at the large volume of exported MEK which has been covertly diverted and used to process cocaine in Latin American countries... 

The importance of tropinone as a possible starting-point for the production of the therapeutically valuable alkaloids atropine, hyoscyamine, cocaine, tropacocaine and the artificial tropeines (p. 73) led Robinson to consider the possibility of preparing this substance by a simple method. Starting with the idea that the formula for tropinone (XXX) may be regarded as made up of the formulae of the residues of succindialdehyde (XXVII), methylamine (XXV III) and acetone (XXIX), he found that a mixture of these substances in water, when allowed to stand for thirty minutes produced tropinone, which could be detected by means of its characteristic dipiperonylidene derivative (bright yellow needles, m.p. 214°). 

The liabitat of Erythroxylon spp. is principally the western side of Soutl America, and although indigenous species occur in India, Africa anc Australia, they have no economic value. Two kinds of coca leaves ar< available in commerce, Bolivian or Huanuco leaves derived from E. coce Lam. and Peruvian or Truxillo leaves obtained from E. truxillense Rusby both are cultivated in Java. In South America coca leaves are chewee with lime by the Indians as a stimulant, and are exported to Europe foi use in medicine and for the preparation of cocaine, but the prineipal sourc< of coca leaves is Java. Crude cocaine is manufactured in South Americi and exported for refining and some aspects of this industry have beei discussed recently. ... 

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

Cocaine has been prepared by a sequence beginning w ith a Mannich reaclion (Problem 23.63) between dimethyl acetonedicarboxylate, an amine, and a dialdehyde. Show the structures of the amine and dialdehyde. 

Cocaine metabolites (e.g., ecogonine, benzoylecogonine, etc.) 30 m DB-5 column, 200-280° at 107min. (Preparation of methyl ester and TMS derivatives is recommended.)... 

In Britain and America the most common form of cocaine is as a white crystalline powder. Most users sniff it up the nose, often through a rolled banknote or straw, but it can also be made into a solution and injected. Crack is a smokable form of cocaine made into small lumps or rocks . It is usually smoked but can also be prepared for injection. Because it is such a fast-acting drug and the powerful effects wear off quickly, repeated use is common, and since cocaine is a relatively expensive drug it has become closely associated with a rich lifestyle. 

The basic principle of the synthesis involving 143 has been applied for the preparation of many tropane derivatives [e.g., 6-hydroxytropinone (144) and ( + )-cocaine (98)] (69-71). During recent years, especially in China, considerable attention has been paid to practical applications and modifications of this long known method (70-77), illustrated here by the scheme leading to anisodamine (63) (Scheme 4). 

One of the most common psychostimulants, cocaine, is derived from the coca plant (Erythroxylon coca) and has a long history as a stimulant. It has been used for centuries in Bolivia and Peru as a tonic and other preparations to alleviate fatigue (Siegel 1985 Hill et al. 1977). 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Scheme 42. Two pathways for the N-demethylation of cocaine by mammalian liver microsomal enzyme preparations.

There have been several studies that underscore the importance of unbound concentration in cell-based studies of receptor function. In a model study of the effect of plasma protein binding on the renal transport of organic anions using the expression of various organic anion transporters (OATPs) in Xenopus oocytes, the transport of ochratoxin A, methotrexate, and estrone sulfate was found to be strongly inhibited by the addition of human serum albumin to the culture medium [16]. Similarly, the addition of oq-acid glycoprotein was found to reverse the blockade of sodium-ion current by cocaine in a preparation of cardiac myocytes [17]. 

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