A model experiment in the study of cocaine base smoking. Isolation of methyl 4-(3-pyridyl) butyrate from cocaine pyrolysate

Sections

ABSTRACT
Introduction
Materials and methods
Results and discussion

Details

Author: M. NOVAK and , C. A. SALEMINK
Pages: 79 to 82
Creation Date: 1984/01/01

A model experiment in the study of cocaine base smoking. Isolation of methyl 4-(3-pyridyl) butyrate from cocaine pyrolysate

M. NOVAK and
C. A. SALEMINK
Laboratory of Organic Chemistry, State University, Utrecht, The Netherlands

ABSTRACT

Cocaine base was pyrolysed at 600 oC in a nitrogen atmosphere and methyl 4-(3-pyridyl) butyrate was isolated as one of the main components from the cocaine pyrolysate. The structure of the compound was determined by spectral means as well as by comparison with a synthetic sample.

Introduction

Since the early l 970s the practice of sniffing cocaine changed in some countries into smoking this alkaloid in the form of coca paste or cocaine base mixed with tobacco or cannabis (Siegel [1] , Paly and others [2] ). Coca paste is a crude extract of coca leaves and is reported to contain cocaine base along with cocaine salts, other coca alkaloids and traces of residual organic solvents (Paly and others [2] ).

The acute and chronic effects of the smoking of cocaine base and coca paste seem to be far more severe than those usually reported for intranasal cocaine use (Siegel [1] , Paly and others [2] ). Therefore, it is important to have a better understanding of the changes that take place during the smoking process. Pyrolysis of cocaine under nitrogen seemed to be a good model for cocaine smoking, since it was shown (Spronck and others [3] ) that pyrolysis of cannabinoids under nitrogen gives similar results to the smoking of cannabis mixed with tobacco. This is the first investigation of the pyrolysis of cocaine (1).

Materials and methods

Proton nuclear magnetic resonance ( 1H-NMR) spectra were recorded in CDC1 3 on a Varian EM-390 spectrometer with tetramethylsilane as an internal standard. Mass spectra (MS) were taken with a Kratos MS 80 spectrometer. Gas chromatographic analyses were carried out using a Becker 409 chromatograph and 3 per cent OV-17 column. The pyrolysis apparatus is shown in the figure.

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In each experiment 20 mg cocaine base (l ) was deposited as a thin film on the inner wall of the larger diameter part of the pyrolysis tube. The tube was connected to a gas control unit and nitrogen was passed through (25 ml/min). The smaller diameter part of the pyrolysis tube was inserted through the oven (600 o C) and connected to the cold trap. The oven was moved fully to the right. After five minutes the oven was moved over the larger diameter part of the tube (this is the position shown in the figure). After pyrolysing for five minutes the tube and the cold trap were rinsed with absolute ethanol.

An amount of 85 mg pyrolysate was partitioned between chloroform and saturated bicarbonate solution. The chloroform fraction showed on thin layer chromatography (TLC) (silica gel 60 F 254, Merck), using ethylacetate/methanol / water / concentrated ammonia (85/13/1/0.5) as the developing system, two main spots with R f values of 0.43 (cocaine) and 0.49, detected by ultraviolet light. The compound with R f value 0.49 was isolated by preparative TLC (silica gel 60 F 254, Merck) of the whole chloroform fraction using the same solvent mixture as above. The required zone was located under ultraviolet light, scraped and eluted with absolute ethanol, to yield an oily residue (6 mg, yield 7 per cent pure by gas liquid chromatography (GLC), RRT 0.05 in relation to cocaine using 3 per cent OV-17 column at 200 o C). The isolated compound was identified as methyl 4-(3-pyridyl) butyrate (2) according to the 1H-NM R and MS data:

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1H-NM R (CDC13) delt 8.45 (m, 2 H), delt 7.5 (m, l H), delt 7.2 (m, l H), delt 3.7 (s, 3 H), delt 2.65 (t, 2 H), delt 2.3 (m, 2 J) and delt l .95 (m, 2 H). MS : M + 179 (4 per cent), 148 (13 per cent), 120 (4 per cent), 106 (100 per cent), 92 (20 per cent), 78 (3 per cent), 74 (1 3 per cent), 65 (l 3 per cent) and 59 (3 per cent).

The spectral and GLC data were identical with those of a sample synthesized according to the literature. As starting material, 3-(3-pyridyl)propane-l-ol (3) (Aldrich) was used, which was converted with thionyl chloride into 3-(3-chloropropyl)-pyridine (4) (Eisch, Gopal and Russo (4). After a chain extension with sodium cyanide in dimethyl sulphoxide the obtained 4-(3-pyridyl)-butyronitrile (5) (Carlson and others [5] ) was hydrolyzed in hydrochloric acid to 4-(3-pyridyl) butiric acid (6) (Carlson and others [5] ). Esterification of this acid with sulphuric acid in methanol yielded the methyl ester (2) (Schwartz and McKennis [6] ).

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Results and discussion

Methyl 4-(3-pyridyl) butyrate (2) was isolated as one of the main components of the cocaine pyrolysate and could be considered a rearrangement product of the cocaine molecule. The pharmacological effects of this compound have not yet been investigated. The isolated compound could, however, be of importance in explaining the severe effects caused by cocaine smoking. Therefore, the pharmacological effects of this ester should be tested, whether or not in combination with cocaine.

It is interesting to mention that the acid (6) shows hypolipidemic activity. It inhibits the noradrenaline-induced free fatty acid mobilization in the dog (Carlson and others [5] ).

References

01

R. K. Siegel, "Cocaine smoking", New England Journal of Medicine , 1979,

00

pp. 300 - 373.

02

D. paly and others, "Plasma cocaine concentrations during cocaine paste smoking" , Life Sciences , No. 30, 1982, pp. 731 - 738.

03

H. J. W. Spronck and others, "Pyrolysis of cannabinoids: a model experiment in the study of cannabis smoking", Bulletin on Narcotics (United Nations publication), Vol. XXX, No. 3 (1978), pp. 55 - 59.

04

J. J. Eisch, H. Gopal and D. A. Russo, "Preparation and aluminum chloride induced rearrangement of cyclopropylpyridine", Journal of Organic Chemistry. No. 39, 1974, pp. 31 10 - 31 14.

05

L. A. Carlson and others, "Potential hypolipidemic agents V. syntheses of some new 3-substituted pyridines: effects on noradrenaline-stimulated free fatty acid mobilization", Acta Pharmaceutica Suecica , No. 9, 1972, pp. 405 - 410.

06

S. L. Schwartz and H. McKennis, Jr., "Studies on the degradation of the pyrolidine ring of (- )-nicotine in vivo", Journal of Biological Chemistry, No. 238, 1963, pp. 1807 - 1812.