Ecgonine, methyl

Benzoylation.—Distilled methyl-ecgonine dissolved in benzene is mixed with a small excess of benzoyl chloride, and the mixture heated at its boiling point under a reflux condenser. The cocaine hydrochloride obtained on cooling is converted to base and is purified by recrystallisation from alcohol. The hydrochloride is then re-formed and recrystallised from mixtures of alcohol and light petroleum or ether. Recrystallisation must be repeated, if necessary, until the pharmacopoeial tests of purity are complied with, since associated impurities are apt to possess dangerous toxic properties. 

Benzoyl-ecgonine-methyl-ester Benzol-methyl-ecgonine Cocainum Cocaine, Fr. Cod. Cocain, Kokain, G. 

Pharmacol, 1, 1004-1011 (1955). Cited in Perrin 2862 ref. C27. NB The study used measurements of pH witti a glass electrode. See also Jensen HH, Lyngbye L, Jensen A and Bols M, Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines, Chem. Eur. /., 8(5), 1218-1226 (2002). This paper reported pJmore than 60 other piperidines or closely related compounds. 

Scheme 6. Classical (path C) and revised proposals (path D) for the biosynthesis of methyl ecgonine 19 and thence of cocaine the illustrated incorporation experiment with [ N, C] 10 supported path D...

The situation is different in the case of methyl ecgonine (19) in which the carboxyl carbon of the putative intermediate (25) is retained. Methyl ecgonine isolated from Erythroxylon coca plants is optically active, it is the (-) antipode of (2R,3S) absolute stereochemistry, and for the purposes of this discussion we shall surmise for simplicity that it is optically pure. Cocaine isolated from plants to which rac-[l,2- C2,l- C] -(22) had been supplied shows only one labeling... 

This result suggests that only the (S) enantiomer of (22) serves as a precursor for (-) methyl ecgonine. Unfortunately, the authors did not investigate the fate of (R)-(22) in the plant during the feeding experiments. It remains unclear whether the latter simply accumulates within the plant or whether it is oxidized to (R)-... 

Scheme 12. Biosynthesis of cocaine via methyl ecgonine 19 only the (2J, 3S)-enantiomer is formed...

Figure 8.16 Yields of cocaine-content pastelike plant extract can be increased by treating it with hydrochloric acid to hydrolyze the extract to ecgonine. Treatment with boron chloride in methanol produces methyl ecgonine, which is converted to cocaine by the addition of benzoyl chloride and benzene. 

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. 

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°. 

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-... 

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. 

Ecgonine + Methyl Iodide + Benzoic Anhydride---- COCAINE... 

Fig. 7.8. The hydrolytic metabolism of cocaine (7.57) to form benzoylecgonine (7.58), ecgo-nine methyl ester (7.59), and ecgonine (7.60). In the presence of ethanol, benzoylecgonine ethylester (7.61, cocaethylene) is also formed enzymatically as discussed in the text.

S. M. Roberts, R. D. Harbison, R. C. James, Inhibition by Ethanol of the Metabolism of Cocaine to Benzoylecgonine and Ecgonine Methyl Ester in Mouse and Human Liver , Drug Metab. Dispos. 1993, 21, 537-541. 

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