Ecgonines

Ci-,H2,N04. Colourless prisms, m.p. 98°C. Obtained from coca, either by direct purification, or by acid hydrolysis of the mixed alkaloids to ecgonine, which is then methylated and benzoylated. Coca consists of the dried leaves of Eryihroxyluni coca and Erythroxylum iruxillense, shrubs growing in Bolivia and Peru. 

Cocaine is the oldest of the local anaesthetics. It is a central nervous system stimulant and is habit-forming. See ecgonine. 

Thus the ecgonin methyl ester fragment J ean elearly be reeognised only the link to the O atom still remains to be established. The attaehment of the O atom is identified by the large ehemieal shift value (Sfj = 5.59) of the proton on the same earbon atom. The parts A and J then give the skeleton K of eoeaine. 

When heated with mineral acids Z-cocaine is hydrolysed into Z-ecgonine (p. 96), benzoic acid and methyl alcohol and a like change takes place with baryta water. If the alkaloid is boiled with water, methyl alcohol is split off and a new base, benzoyl-Z-ecgonine is formed, which in turn can be hydrolysed by acids or alkalis into Z-ecgoninc and benzoic acid. Cocaine is, therefore, methylbenzoyl-Z-ecgonine. 

The isomeric -cinnamylcocaine (methylcinnamoyl-d- -ecgonine) prepared by Einhorn and Deckers by the action of cinnamoyl chloride at 150-60° on d-i/r-ecgonine methyl ester, crystallises in prisms, m.p. 68°, [ Id + 2° (EtOH). The hydrochloride, B. HCl, forms needles, m.p. 186° the platinichloride, needles, m.p. 208°, and the aurichloride orange needles, m.p. 164°. 

Z-Ecgonine, CgHigOgN. HjO. This substance was first obtained I Lossen as the final basic hydrolytic product of the action of acids c cocaine, and is obtainable in like manner from several of the alkaloii occurring with cocaine (see above). It crystallises from dry alcohol i monoclinic prisms, m.p. 198° (dec.), 205° (dry), [a]n — 45-4°, is soluble i water, sparingly so in alcohol, insoluble in most organic liquid Eegonine forms Salts with bases and acids the hydrochloride crystallis... 

The close relationship of eegonine to tropine is brought out by its Oxidation products, which when chromic anhydride in acetic acid is the agent used are tropinone, CgHijON (p. 74), tropinic acid, CgHi304N (P- 75) and ecgoninic acid, C HnOgN. The latter crystallises from benzene in colourless needles, m.p. 93°, and has been shown by Willstatter and Bode to W-methylpyrrolidone-2-acetic acid, and this was confirmed by Willstatter and Hollander s synthesis of the acid. 

The close relationship existing between ecgonine and tropine is eviden from the following diagrammatic summary of the results of reactions... 

Tropine CgHijON —Tropigenine C,Hj30N Ecgonine C3Hj503N —noiEcgonine CgHi303N Exhaustive Methy lation ... 

There are two probable formulae (II) and (HI) for ecgonine derivable from Willstatter s representation of tropine (p. 76). 

Accepting this view of the constitution of ecgonine, the formulae of its derivatives and of cocaine may be written as follows anhydroecgoninc (VII), ecgonine (VIII), norecgonine (IX) and cocaine (X). 

Willstatter and Bode converted tropinone into (/(-ecgonine by treating sodium tropinone with carbon dioxide and sodium, when it yielded sodium tropinonecarboxylate. This on reduction with sodium in alcohol gave some dZ-i/i-ecgonine (p. 97), which on esterification with methyl alcohol and benzoylation yielded a dhcocainc. A simpler synthesis of ( -eegonine was achieved by Willstatter and Bommer, and reference is made on p, 80 to this and other processes, some of which have been protected by patents. These improvements having enabled the prepara-... 

These investigations have followed three main lines, (1) alterations in the amino-alcohol nucleus, (2) variation in the alkyl or acyl side-chains, (3) influence of stereoisomerism. Tropine and ecgonine, the basic components of atropine and cocaine, lend themselves to such investigations, but scopine, the amino-alcohol of hyoscine is so labile that systematic modification of this alkaloid has not yet been possible. 

Stereoisomerism in either the alkamine nucleus or the acyl residue has a considerable effect on the pharmacological action of the tropeines and cocaines. Differences in activity of tropine and i/i-tropine and their benzoyl derivatives have been mentioned already, and there seems to be a consensus of opinion that the i/i-cocaines (alkyl- or aryl- acyl esters of 0-ecgonine) are less toxic and more potent local anfesthetics than the corresponding cocaines, derived from 1-ecgonine. ... 

Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready themnal decarboxylation to tropinone (4)The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently. Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine. Reduction, esterification with methanol followed by benzoylation then affords cocaine. 

Alkaloids, e.g. cocaine, ecgonine, benzoylecgonine, ecgonine methyl ester 280 °C, 8 min or 260°C, 10-30 min Pale blue induced fluorescence (Xn > 390 nm, cut off filter), fluorescence amplification by a factor of 2 on dipping in liquid paraffin solution detection limits <10 ng. [13]... 

Cocaine, ecgonine, ecgonine methyl ester, benzoylecgonine ... 

Fig. I Fluorescence scan of a chromatogram zone with 300 ng each of ecgonine methyl ester (1), cocaine (2), ecgonine (3) and benzoylecgonine (4) per chromatogram zone.

Phthalate esters are widespread contaminants and the dialkyl phthalates are hydrolyzed before degradation of the resulting phthalate (Eaton and Ribbons 1982), which is discussed in Chapter 8, Part 3. For dimethyl phthalate, dimethyl terephthalate, and dimethyl isophthalate only partial hydrolysis may take place (Li et al. 2005). Cocaine is hydrolyzed to benzoate and ecgonine methyl ester by a strain of Pseudomonas maltophilia (Britt et al. 1992). 

However, there are some data on interactions of phosphate esters with other compounds. Cocaine undergoes metabolism by three major routes one of these routes involves hydrolysis by liver and plasma cholinesterases to form ecgonine methyl ester. It has been suggested that cocaine users with serious complications tend to have lower plasma cholinesterase levels. Thus, it is possible that individuals with decreased plasma cholinesterase levels (such as resulting from organophosphate ester exposure) may be highly sensitive to cocaine (Cregler and Mark 1986 Hoffman et al. 1992). However, there are no experimental data to support this hypothesis. 

---