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The Isolation and Identification of Precursors
and Reaction Products In the Clandestine
Manufacture of Methaqualone and Mecloqualone

S. A. Angelos and J. A. Meyers
J. Forens. Sci. 30(4), 1022-1047 (1985)

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Abstract

Abuse of the hypnotic quinazolinone is well recognized and increasing. Clandestine laboratories producing methaqualone (2-methyl-3-ortho-tolyl-4(3H)quinazolinone) and mecloqualone (2-methyl-3-ortho-chlorophenyl-4(3H)quinazolinone) have been discovered throughout the United States. These laboratories utilize one of many synthesis routes to produce the illicit quinazolinone. Frequently, the clandestine chemist has little, if any, formal education in chemistry; does not keep notes; and does not label flasks and beakers containing solutions. The forensic chemist may be asked to analyze unmarked reaction mixtures that were seized in a clandestine laboratory raid. As a result, a rapid method of isolation and identification of the precursors and products of such a mixture is presented.

The drugs methaqualone (2-methyl-3-ortho-tolyl-4(3H)-quinazolinone) and mecloqualone (2-methyl-3-ortho-chloro-phenyl-4(3H)-quinazolinone) have been manufactured in clandestine laboratories in the United States. A rapid method of isolation and identification of the precursors and products of clandestine mixtures is presented. Gas-liquid chromatographic and high pressure liquid chromatographic separations are described. Infrared, nuclear magnetic resonance, and mass spectra of the compounds identified are provided.

The abuse potential of the hypnotic drug methaqualone1 and its chlorinated analogue, mecloqualone2, is recognized. The source of illegal methaqualone is either from legitimate pharmaceutical firms diverted to the illicit market or from clandestine manufacture. Mecloqualone is not available commercially in the United States but has been produced clandestinely. Currently, there are no legitimate manufacturers of either drug in the United States.

Historically, methaqualone (2-methyl-3-ortho-tolyl-4(3H)-quinazolinone) was first prepared in 19513. Studies of its metabolism in man were reported in 19604-6, and in animals in 19637. Methaqualone was introduced pharmaceutically as a nonbarbiturate, nonaddictive, "sleeping pill" in 1965. Recently (1976) metabolite detection for forensic science purposes has been reported8. Methaqualone has been controlled in the Federal Comprehensive Controlled Substances Act of 1970 (P.L.91-513) since 4 Oct. 1973 (38 FR27516). As of 27 Aug. 1984, methaqualone has been moved from Schedule H to Schedule I within the Federal Act.

Mecloqualone (2-methyl-3-ortho-chlorophenyl-4(3H)-quinazolinone) was first prepared in 19609. Metabolism studies were reported in man in 197410. Since mecloqualone has nocurrent medical use in the United States, it has been federally controlled as a Schedule I drug since 10 Sept. 1975 (40 FR28611). In Europe, mecloqualone is available as a hypnotic.

The reported synthetic routes for these quinazolinones are uncomplicated one- or two-step procedures that can be performed in clandestine laboratories without difficulty. Laboratories producing the illicit quinazolinones have been discovered throughout the United States. The forensic chemist frequently is asked to analyze unlabelled reaction mixtures from laboratory seizures. The identification of the precursors and by-products of such a reaction mixture would aid the forensic chemist in determining the synthetic route used in the illicit production.


Table 1. List of compounds
Compound
Formula
M.W.
Chemical Name
I
C7H7NO2
137
Anthranilic acid
II
C9H9NO3
179
N-Acetylanthranilic acid
III
C7H9N
107
o-Toluidine
IV
C6H6ClN
127
o-Chloroaniline
V
C16H14N2O
250
Methaqualone
VI
C15H11ClN2O
270
Mecloqualone
VII
C9H10NO
149
o-Methylacetanilide
VIII
C8H8ClNO
169
o-Chloroacetanilide
IX
C16H12N2O3
280
2-Methyl-3-(o-carboxy-
phenyl)-4-quinazolinone

Synthetic Methods

Two basic methods for the clandestine manufacture of either methaqualone or mecloqualone have been encountered. The first method is a two-step reaction that involves the preparation of N-acetylanthranilic acid (II) (Table I) from anthranilic acid and acetic anhydride followed by condensation with either o-toluidine (III) to produce methaqualone (V) or o-chloroaniline (IV) to produce mecloqualone (VI). Phosphorus trichloride is used to remove water produced in the reaction3.

The second method is carried out in a one-step reaction by refluxing anthranilic acid (I), o-toluidine (III), and acetic acid (or acetic anhydride). Polyphosphoric acid may be added to remove water. Purification is accomplished by dissolving the solid residue in methanol and precipitating the hydrochloride salt from a methanol-diethyl ether solution.

Experimental

Chromatographic separations of the reactants and by-products were performed by both high pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC). A Waters Associates HPLC equipped with an ultraviolet (254-nm) detector, fitted with a 30-cm by 3.9-mm inside diameter (ID) Bondapak C18 column a mobile phase of 40% methanol-water with 1% acetic acid and methanesulfonic acid (CIPIC reagent) at a flow rate of 2 mL/min was used. Table 2 gives the retention times of various compounds.

Gas-liquid chromatography was performed on a Hewlett-Packard 5840A equipped with 1.8-m (6-ft) 4-mm ID glass columns packed with 10% OV-101 and 3% OV-17 both on Gas Chrom Q. For the 10% OV-101 column, the initial temperature of 150°C is maintained for 3 min and then programmed to increase at a rate of 20°C per minute until a temperature 280°C is reached. For the 3% OV-17 column, the initial temperature of 150°C is maintained for 1 min, and then programmed to increase at a rate of 10°C per minute until a temperature of 280°C is reached. These somewhat complex programs allow for the elution of both reactants and by-products. Table 3 gives the actual retention times of the compounds, while Table 4 and Table 5 give the relative retention times for the compounds related to methaqualone and mecloqualone, respectively.

Infrared spectroscopy was performed with a Perkin-Elmer 283 spectrophotometer, utilizing the standard KBr disk method. Liquid samples were prepared as thin films between two KBr disks. Figure 1 provides the infrared (IR) spectra of Compounds I to IX.

Fig. 1: Cpd. I-II | Cpd. III-VI | Cpd. VII-VIII | Cpd. IX

A Finnigan Model 4530 Quadropole gas chromatograph-mass spectrometer (GC/MS/DS) was used to obtain the mass spectra. The chromatographic system used, was 1.8-m (6-ft) 2-mm ID glass column of 0.5% OV-101 on Gas Chrom Q, with a temperature program from 100 to 280°C at a rate of 20°C per minute, (Fig. 2).

Fig. 2: Cpd. I-III | Cpd. IV-VII | Cpd. VIII-IX

Proton magnetic resonance spectra were run on the free base compounds dissolved in deuterated dimethylsulfoxide (DMSO) using a 90-MHz Varian EM 390 spectrometer (Fig. 3).

Fig. 3: Cpd I | Cpd II | Cpd III | Cpd IV | Cpd V | Cpd VI | Cpd VII | Cpd VIII | Cpd IX

Discussion

Clandestine laboratory operators generally spend little or no time purifying the "final product", thus, many impurities and side products can be identified in the forensic science laboratories. The starting reactants anthranilic acid (I) and o-toluidine (III) in the case of methaqualone (V) would be present. Normally o-toluidine is found in relatively large amounts. Additionally the intermediate N-acetyl anthranilic acid (II) can be used as an indicator of the success of the reaction, in that a large amount in the sample would imply a low yield of the quinazolinone.

The intermediates and by-products found in a clandestine mixture are useful in identifying the synthesis route. For example, o-methyl acetanilide would only be found in a reaction mixture of anthranilic acid, o-toluidine, and acetic anhydride. If N-acetyl-anthranilic acid is produced, isolated, and then reacted with o-toluidine, the o-methyl acetanilide would not be formed. Because of the reactivity of acetic anhydride, several other compounds can be predicted, as any basic compound will undergo nucleophilic substitution with the unreacted acetic anhydride. Initially, there would be a competition between anthranilic acid and o-toluidine, for the available acetic anhydride which would determine the extent of the formation of these by-products. If the original reaction was not shifted towards the product N-acetylanthranilic acid, the yield of methaqualone would be appreciably reduced. Additionally, the production of o-methyl acetanilide gives rise to additional by-products and further reduces the yield of methaqualone by removing o-toluidine from the reaction.

The by-product 2-methyl-3-(o-carboxyphenyl)-4-quinazolinone is formed by the condensation of anthranilic acid and N-acetyl-anthranilic acid. This carboxy analogue can be formed whether methaqualone is being produced, and is in competition with its formation. The presence of this analogue would indicate the synthesis route starting with anthranilic acid. Mixtures of methaqualone, mecloqualone, or the carboxy analogue cannot be differentiated by ultraviolet spectroscopy (UV), which could result in an error if UV is used for quantitation. Methanolic solutions of actual clandestine methaqualone reaction mixtures were used in the gas chromatograph-mass spectrometry study. The solutions were found to contain large amounts of methaqualone, moderate amounts of o-methyl acetanilide (VII) and 2-methyl-3-o-carboxyphenyl-4(3H)-quinazolinone (IX), and small amounts of o-toluidine.


Conclusions

The methods described can be very important tools to successful prosecution of an illicit drug manufacturer. Consideration should also be given to application of these methods on the finished product, "street samples."

Since the final product of clandestine laboratories can vary from a purified drug to a combination of starting ingredients, by-products, and the desired drugs it may be important to identify as many components as possible in the sample. This can give an indication of the synthesis route employed or the sophistication of the "chemist" or both. The results of the analysis can be used for intelligence purposes as a possible basis for comparison with other samples, which could lead, in turn, to identification of trafficking routes and possible sources of illicit drugs.

References

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  2. Drug Enforcement Administration, Federal Register, Vol. 40, No. 131, 28611 (1975)
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