element109
(Hive Bee)
04-16-02 10:19
No 297760
      cocaine ref digged up
(Rated as: excellent)
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From:
REC. TRAV. CHIM. PAYS-BAS (1940) 59, p. 27


             COMPLETE CONVERSION OF l-ECGONINE METHYL ESTER INTO l-COCAINE


         by  A. W. K. DE JONG


--------------
A complete conversion is obtained in 10 hours by boiling an anhydrous benzene solution of l-ecgonine methyl ester with benzoyl chloride in the presence of dry sodium carbonate, calcium oxide or a mixture of calcium oxide and hydroxide. In chloroform solution about 20 hours are necessary and in ethereal solution about 40 hours, when a mixture of calcium oxide and hydroxide is used.

--------------

[...]

The well-known esterification method of Schotten-Baumann cannot be used since the methyl ester of ecgonine is very easily decomposed by concentrated alkali solution at ordinary temperature.

When Deninger  [J.prakt.chem. (1894) 50, 479]  stated that benzoic anhydride is formed by heating benzoyl chloride with anhydrous sodium carbonate and a drop of pyridine.

[...]

The presence of water must be avoided since benzoyl chloride as well as l-ecgonine methyl ester are decomposed by boiling them in a solution containing traces of water.

Besides sodium carbonate (obtained by heating fine pulverised sodium carbonate exsiccatus or bicarbonate) calcium oxide and mixtures of calcium oxide with sodium carbonate or calcium hydroxide and the latter admixed with sodium hydroxide, were also used; these last two mixtures were obtained by adding to 25 g of fine pulverised calcium oxide 3.5 ml water or 4 ml 2N sodium hydroxide solution, respectively. As solvent, ether, chloroform and benzene were used. The solutions contained about 1 ml of 0.1N methyl ester in 10 ml.

The experiments were carried out in the following way. To 10 ml of the anhydrous solution 1 g or more of the alkaline compound for absorbing hydrochloric acid and 0.5 ml of benzoyl chloride were added, and the measuring tube washed out with 10 ml of anhydrous solvent. The solution was partly distilled to eliminate possible traces of water and boiled for some hours. The condensor was provided with a calcium chloride tube. The solution was then filtered off and the flask and filter washed three times with anhydrous solvent. It was shaken with about 2 ml 0.1N hydrochloric acid solution + 5 ml water and then twice with 5 ml water. The acid solution was shaken with 25 ml of the solvent to get rid of a trace of benzoyl chloride and the solvent was then shaken twice with 5 ml water. In this way about 27 ml of aqueous solution were obtained.
The excess acid was titrated with methyl red in ether solution as indicator and the quantity of bases present calculated. After saturation with sodium bicarbonate the solution was shaken three times with 15 ml ether. The etheral solution on distillation gave a residue crystallising after inoculation with a trace of cocaine, the quantity being determined by titration.

From the bicarbonate solution unchanged methyl ester can be isolated by shaking nine times with 15 ml of chloroform.

[...]

USING ETHER AS SOLVENT :

(I) = l-ecgonine methyl ester

0.8 ml 0.1N (I) ; 2 g CaO+Ca(OH)2 ; 20 hours :  90% transformed
0.8 ml 0.1N (I) ; 2 g CaO+Ca(OH)2 ; 33 hours :  95% transformed

The transformation is very slow; it takes about 40 hours to complete.


The experiments with chloroform have shown that it is best to dissolve the methyl ester of ecgonine first in benzene and to distill off the solvent from the solution to ensure its being sufficiently anhydrous; [...] The transformation would be complete in about 20 hours.


USING BENZENE AS SOLVENT :

1.25 ml 0.1N (I) ; CaO+Ca(OH)2 ; 7.5 hours :  95% transformed
1.00 ml 0.1N (I) ; calcium oxide ; 10 hours :  100% transformed
0.95 ml 0.1 N (I) ; sodium carbonate ; 10 hours :  100% transformed

Benzene can be obtained sufficiently anhydrous by distilling off until the distillate is no longer cloudy. The conversion is complete in 10 hours.

---------------------------------



e109
 
 
 
 
    element109
(Hive Bee)
04-16-02 10:25
No 297761
      question about the analogs  Bookmark   

Are there any bees here who have read up a bit on cocaine analogs ?

From what i have read so far i understand that :

  * phenyltropanes are more potent than cocaine,
  * 4'-fluorococaine is 60x times more potent
  * 4'-fluorophenyltropane should be even more potent;
  * 4'-halo, methyl, nitro, amino, methoxy all increase potency of phenyltropanes

Please correct me where i'm wrong.
Phenyltropanes are obtained by substituting BzCl for benzoyl ?



e109
 
 
 
 
    Rhodium
(Chief Bee)
04-16-02 18:39
No 297897
      Thank you for bringing that article before my ...  Bookmark   

Thank you for bringing that article before my eyes!

No, that is not the proper way of doing it. See the PDF linked in Post 294273 (Rhodium: "Cocaine Analogs", Novel Discourse) - In scheme I cocaine is treated with 37% HCl and methanol to give anhydroecgonine methyl ester (that is cocaine without the benzoyl group, and with a double bond between where it was and the carboxymethyl group on the tropane part of the molecule. In Scheme III they proceed from anhydroecgonine methyl ester to 3-phenyltropane by treating it with PhMgBr.
 
 
 
 
    SPISSHAK
04-18-02 23:58
      4-FLUOROCOCAINE IS ONLY MORE POTENT IN SEROTONIN
(Rated as: ALL CAPS)
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    Rhodium
(Chief Bee)
04-19-02 01:10
No 299047
      2-Hydroxycocaine
(Rated as: excellent)
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Seems that you are right, SPISSHAK, but you are not allowed to post it in ALL CAPS!

Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter

J Med Chem 40(16), 2474-81 (1997)

Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19, 21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtained from 2'-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4'-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2'-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2'- Hydroxylation also enhanced the bidning potency of 4'-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.
 
 
 
 
    element109
(Hive Bee)
04-19-02 09:41
No 299137
      2'-hydroxycocaine ?  Bookmark   

Rhodium: I'm glad to be of service to you.

I have seen the Chem.Rev. article before but my computer seems to have problems to load it. (it's taking ages..)

What I understand is that the 4'-iodo analog has actually weaker dopamine binding affinities, and that 2'-hydroxy is probably the way to go with it's 10 fold binding potency.

I don't understand much about cocaine's pharmacology but from what I read here: ../rhodium/chemistry/benztropine.txt it seems that increased dopamine receptor activity (blocking reuptake) doesn't always mean increased euphoria?

Nevertheless, that 2'-hydroxy compound seems mighty interesting for pioneering human trials. smile

How would one proceed to hydrogenate the double bond without the ester being reduced?


e109
 
 
 
 
    terbium
(Old P2P Cook)
04-20-02 20:55
No 299683
      I am not sure why one would want to do this.  Bookmark   

I am not sure why one would want to do this. The title of your post implies that you think that hydrogenating anhydroecgonine methyl ester will produce ecgonine methyl ester. It will not, hydrogenating anhydroecgonine methyl ester will produce carbomethoxytropane.