A survey of reported syntheses of methaqualone
and some positional and structural isomers

Etienne F. van Zyl
Forens. Sci. Int. 122, 142-149 (2001)

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Abstract

Methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone) is the illicit synthetic drug of choice amongst South African drug users. Historically police and forensic investigation has proven that all methaqualone seized by the South African Police Service originates from illicit manufacturing sites both inside, and outside South Africas borders. From a drug enforcement, and forensic point of view it is, thus, of utmost importance that the various synthetic routes available to the illicit "chemist" are fully documented and understood. This is a prerequisite for effective illicit laboratory investigation, as well as chemical and precursor monitoring. This paper gives a brief introduction to the current status with regard to methaqualone use and production in South Africa, as well as an extensive review of the synthesis of methaqualone and selected isomers reported since 1946. A table summarizing synthetic routes reported in 32 reference sources is provided.


1. Introduction

Fig. 1.
General structure of 2-alkyl-
3-aryl-4(3H)-quinazolinones.

The synthesis of methaqualone (I, Fig. 1, R1= Me, R2 or R6 = Me, R3=R4=R5=H) was first reported in 19511. It was introduced pharmaceutically as a non barbiturate, nonaddictive "sleeping pills" in 19652. It has been listed in the US Federal Register of March 1966 as an approved sedative-hypnotic with trade name Quaalude3. The abuse potential of methaqualone quickly became apparent resulting in it being listed in the 1971 United Nations (UN) Convention on Psychotropic Substances, and its subsequent banning in most member countries4. Methaqualone is currently listed in the UN Convention on Psychotropic Substances of 1988.

The production, trafficking, and abuse of methaqualone are of particular forensic importance to South Africa as it remains the synthetic drug of choice amongst South African drug abusers5,6. This is illustrated by the fact that methaqualone-seizures amounts to more than 60% of all street-drug seizures submitted to the South African Police Services National Forensic Science Laboratories (SAPS FSL)7. During 1999, a total of 3971 methaqualone-related cases was submitted to the Laboratory, with the cumulative number of dosage units exceeding three million.

Methaqualone was introduced pharmaceutically in South Africa under the trade name "Mandrax", a formulation containing methaqualone (250 mg) and diphenhydramine hydrochloride (25 mg). Following the identification of its abuse potential, methaqualone and its isomers were effectively removed from the legal market in 19715.

All methaqualone seized in South Africa originates from illicit manufacturing sources in the middle-east, south and central Asia, as well as South and southern Africa5. The product is marketed in South Africa as illicit tablet formulations usually in combination with the antihistaminic drug diphenhydramine, and less frequently with the benzodiazepine tranquilliser diazepam. The formulation of methaqualone with diphenhydramine is thought to be historic in nature with illicit producers simply mimicking the original licit "Mandrax" formulation, or by design due to the fact that diphenhydramine inhibits the metabolism of methaqualone8.

Fig. 2.
Generic reaction schemes for the synthesis
of 2,3-disubstituted-4(3H)-quinazolinones.

Methaqualone abuse gives rise to a barbiturate-type dependence9. The most prevalent abuse pattern observed in South Africa is in conjunction with Cannabis6. This involves mixing methaqualone with Cannabis and then smoking it as a so-called "witpyp", i.e. white pipe.

The synthesis of methaqualone usually involves, but is not limited to, uncomplicated one and two step reactions that are easily adapted for illicit synthesis10. Soliman and Soliman11 stated in 1979 that the majority of 2,3-disubstituted 4(3H)-quinazolinones reported in literature have been synthesized via the following generic routes as depicted in Fig. 2:

Fig. 3.
Generic reaction schemes for the synthesis of methaqualone.

In 1985, Angelos and Meyers2 reported that the following two basic synthetic routes for the illicit manufacture of methaqualone have been encountered as depicted in Fig. 3:

A survey of some important synthesis is given by Ramana and Kantharaj12, and can also be found in limited other sources13,14.

The aim of this paper is to provide a complete and detailed literature survey on the reported synthesis of a methaqualone and some positional and structural isomers thereof.


2. Scope of this survey

The target compounds considered for inclusion in this survey where determined based on the following:

Table 1.
Target 4(3H)-quinazolinones (4(3H)-Q) identified in this survey.

No.
Target
MM
R1
R2
R3
R4
R5
R6
I
2-Methyl-3-o-tolyl-4(3H)-Q
250
Me
Me
H
H
H
H
II
2-Methyl-3-m-tolyl-4(3H)-Q
250
Me
H
Me
H
H
H
III
2-Methyl-3-p-tolyl-4(3H)-Q
250
Me
H
H
Me
H
H
IV
3-(2,3-Dimethylphenyl)-4(3H)-Q
250
H
Me
Me
H
H
H
V
3-(2,4-Dimethylphenyl)-4(3H)-Q
250
H
Me
H
Me
H
H
VI
2-Ethyl-3-phenyl-4(3H)-Q
250
Et
H
H
H
H
H
VII
3-o-Ethylphenyl-4(3H)-Q
250
H
Et
H
H
H
H

Table 1 list the specific target compounds identified during this survey.


3. Survey

The survey encompasses 32 published papers and registered patents, detailing 39 reported synthesis. In 1946 Grimmel et al.15 reported the synthesis of inter alia compound III, starting from N-acetylanthranilic acid and p-toluidine in the presence of PCl3. This general procedure of condensing a N-acylanthranilic acid with a substituted or unsubstituted aromatic amine, usually in the presence of PCl3, POCl3, or polyphosphoric acid is reported a further 11 times in literature1,10-12,16-22.

Similar to the above route is synthesis of I starting with the hydrochloride salt of o-toluidine which was reported in Dutch Patent 295,501 in 196523, or alternatively by starting with the sodium salt of the N-acylanthranilic acid which was reported by Rawat24 in 1988.

Synthesis starting from anthranilic acid which is acylated and reacted with an aromatic amine was reported in196016, with a further four reports since18,25-27. These proceed via either a one-, or a two-step route, with the intermediates being either N-acylanthranilic acid or acylanthranil depending on the work-up.

Acetanthranil as a precursor for synthesis was reported on in 1963 by Boltze et al.17, with two more reports since28,29. These routes all involved condensation with a substituted primary aromatic amine to yield the target 4(3H)-quinazolinone.

Manhas et al.30 reported the synthesis of I·HCl starting from isatoic anhydride, o-toluidine, and an acetylating agent, detailing a one- and a two-step route. It was subsequently reported twice31,32.

The synthesis of III from p-methylacetophenone oxime and methylanthranilate was reported by Stephen et al.33 in 1956. This reaction proceeded via the di-o-tolylacetamidine intermediate and SOCl2 was used as a reagent.

In 1961, Grammaticakis34 reported on the synthesis of I, II, and III starting from the corresponding N-tolyl-o-nitrobenzamide and an acetylating agent. The synthesis proceeded via the N-substituted-o-aminobenzamide and the N-substituted-o-acylaminobenzamide. Miyata et al.35 reported the synthesis of I starting from N-o-tolyl-o-aminobenzamide and an acetylating agent in 1997.

In Austrian Patent 235,839 (1964), Ecsery et al.36 reported on the preparation of I starting with N-acetylanthranilic acid and various N-o-tolyl compounds, including isocyanate, isothiocyanate, urea, thiourea, thiourethane, and dithiourethane.

The synthesis of I from methylanthranilate, (MgBr)2-N-o-toluidine, and acetic anhydride via N-o-tolylanthranilamide were reported in 196537. In 1967 Hurmer and Vernin38 reported the synthesis of VII·HCl from o-ethylphenyl-
anthranilamide and o-ethylformate, as well as from anthranilic acid and N-formyl-o-ethylaniline. Kozhevnikov et al.39 subsequently reported the synthesis of VI from N-propionyl- o-methylanthranilate and N,N-dimagnesiumhalido- aniline in 1969.

The preparation of I-d4 from phtalimide-3,4,5,6-d4, acetic anhydride and o-toluidine was described by Fentiman and Foltz40 in 1976. The synthesis proceeded via anthranilic acid and N-acetylanthranilic acid intermediates.

In 1980, Nielsen and Pederson41 reported on the synthesis of I from N-acetylanthranilate and o-toluidine hydrochloride in the presence of N,N-dimethyl-
cyclohexylamine. Hilmy et al.42 reported on the synthesis of I, II, and III from o-toluidine hydrochloride and 2-acetylamino-
benzonitrile in the presence of N,N-dimethyl-
cyclohexylamine hydrochloride. A summary of this survey is given in Table 2.


4. Summary

The most reported synthetic routes for 4(3H)-quinazolinones involve the condensation of a primary aromatic amine, or salts thereof, with acylanthranilic acid, or acylanthranil. These compounds are either used as precursors, or prepared as intermediates, or in situ from anthranilic acid.

The second most reported route involves the reaction of isatoic anhydride with a primary aromatic amine and an acylating agent in either a one, or a two-step reaction. A third type of synthesis involves the cyclization of o-acylamino (N-substituted) benzamides. Some other more exotic synthetic approaches have been reported in literature, and many more should be possible. Due to the intricate and/or tedious nature of such routes, the author is of the opinion that it is unlikely that these will be encountered at illicit laboratories.

The data provided in Table 2 can effectively be used as a reference source for forensic scientists investigating illicit methaqualone manufacturing sites, and exhibit material originating from such sites. It furthermore provides a detailed list of precursors and chemicals that needs to be controlled and/or monitored in order to assist in the curbing of illicit methaqualone production.

Table 2.
Summary of reported synthesis of some 4(3H)-quinazolinones

#
Ref
Year
Ta
Precursors
Reagents
Solvents
Yield
1
[15]
1946
III
N-acetylanthranilic acid MePh
68%
p-Toluidine PCl3
  Na2CO3
2
[1]
1951
I
II
IV
N-acetylanthranilic acid MePh
I
48%

II
60%

IV
80%
o-Toluidine PCl3
m-Toluidine Na2CO3
N-propionylanthranilic acid EtOH
Aniline
3
[33]
1956
III
p-Methylacetophenone
oxime
SOCl2
69%
CHCl3
Methylanthranilate Alkalizing
agent
4
[16]
1960
I
N-acetylanthranilic acid MePh
80%
POCl3
  NaOH
o-Toluidine HCl
EtOH
5
[16]
1960
I
Anthranilic acid HCl
70%
Acetic anhydride NaOH
o-Toluidine Carbon
  EtOH
6
[34]
1961
I
II
III
N-o-tolyl-o-nitrobenzamide SOCl2, or
-
N-m-tolyl-o-nitrobenzamide H2SO4, or
N-p-tolyl-o-nitrobenzamide (CH3COO)2O
Acetylating agent
7
[17]
1963
I
Acetanthranil Ph-H/Me/Cl
74%
o-Toluidine K2CO3
EtOH/i-PrOH
8
[17]
1963
I
N-acetylanthranilic acid MePh
74%
o-Toluidine PCl3
  EtOH/i-PrOH
9
[36]
1964
I
N-acetylanthranilic acid Xylene

or

PhNO2
-
N-o-tolylisocyanate, or
N-o-tolylisothiocyanate, or
N-o-tolylurea, or
N-o-tolylthiourea, or
N-o-tolylthiourethane, or
N-o-tolyldithiourethane
10
[28]
1965
I
Acetylanthranil None
45%
o-Toluidine
11
[18]
1965
I
N-acetylanthranilic acid H3PO4
-
Activated C
o-Toluidine Na2CO3
MeOH
12
[18]
1965
I
Anthranilic acid H3PO4
62%
Acetic acid Activated C
o-Toluidine Na2CO3
  MeOH
13
[25]
1965
I

VI
Anthranilic acid PhCl
I
90%

VI
91.5%
Acetic anhydride POCl3
o-Toluidine NaOH
Propionic anhydride Na2CO3
Aniline HCl
  Activated C
14
[23]
1965
I

I
(HCl)
N-acetylanthranilic acid HCl
I·HCl
72%
NaOH
o-Toluidine·HCl EtOH
Et2O
15
[37]
1965
I
Methylanthranilate NaOAc
95.3%
N,N-dimagnesium-
bromido-o-toluidine
NaOH
(calcinated)
Acetic anhydride EtOH
16
[26]
1966
I
Anthranilic acid H3PO4
-
P2O5
Acetic anhydride Na2CO3
HCl
O-Toluidine Activated C
NH4OH
17
[38]
1967
VI

I
(HCl)
N-formylanthranilic acid MePh
-
POCl3
o-Ethylaniline EtOH
HCl
18
[38]
1967
VII
(HCl)
Anthranilic acid Na2CO3
-
N-formyl-o-ethylaniline HCl
19
[38]
1967
VII
(HCl)
o-Ethylphenyl-
anthranilamide
HCl
-
O-Ethylformate
20
[39]
1969
VI
N-propionyl-
o-methylanthranilate
None
85%
N,N-dimagnesium-
halidoaniline
21
[27]
1969
I
Anthranilic acid MePh
87%
Acetic anhydride PCl3
o-Toluidine NaOH
  EtOH
22
[29]
1976
III
Acetanthranil Benzene
or
Et2O
-
o-Toluidine
p-Toluidine Basifying
agent
23
[40]
1976
I-d
Phtalimide-3,4,5,6-d4 NaOH/Br2/HCl
-
Acetic acid
Acetic anhydride MePh/POCl3
Na2CO3/MeOH
o-Toluidine Activated C
Hexane
24
[30]
1977
I
(HCl)
Isatoic anhydride Et2O
85%
o-Toluidine CH2Cl2 or
Hexane
EtOH
Acetylacetone HCl
25
[30]
1977
I
(HCl)
Isatoic anhydride MePh
80%
o-Toluidine HCl
Acetylacetone
26
[19]
1978
I
N-acetylanthranilic acid BrPh
48.4%
Benzene
HCl
  Et2O
O-Toluidine NaOH
Benzene or
Pet. Ether
27
[20]
1979
I
N-acetylanthranilic acid POCl3
-
O-Toluidine MePh
  Basifying
agent
28
[11]
1979
I
N-acetylanthranilic acid
-
60%
O-Toluidine
29
[31]
1980
I
Isatoic anhydride
Basifying
&
Acidifying
agents
-
Acetylating agent
O-Toluidine
30
[31]
1980
I
Isatoic anhydride POCl3
-
O-Toluidine
Acetic anhydride
31
[41]
1980
I
N-acetylanthranilate P2O5
84%
N,N-dimethyl-
cyclohexyl-
amine
o-Toluidine·HCl NaOH
CH2Cl2/EtOH
32
[10]
1981
I
II
III
N-acetylanthranilic acid MePh
-
o-Toluidine PCl3
m-Toluidine MeOH
p-Toluidine CHCl3
  HCl/NaOH
33
[21]
1984
I
(HCl)
N-acetylanthranilic acid MePh
I·HCl
76%
O-Toluidine CHCl3/POCl3
  MeOH/Acetone
34
[42]
1987
I
II
III
o-Toluidine·HCl P2O5
I
53%

II
40%

III
33%
2-Acetylaminobenzonitrile N,N-Dimethyl-
cyclohexyl-
amine·HCl
  NaOH
CH2Cl2/MeOH
35
[24]
1988
I
Sodium
N-acetylanthranilate
MePh
-
o-Toluidine PCl3
36
[22]
1990
I
II
N-acetylanthranilic acid MePh/PCl3
I
22.8%
o-Toluidine NaHCO3
p-Toluidine CHCl3/MgSO4
  i-PrOH
37
[12]
1994
I
II
VII
N-acetylanthranilic acid TosCl/Pyridine
I
75%

II
80%

VII
68%
o-Toluidine NaHCO3
m-Toluidine CH2Cl2
N-propionylanthranilic acid Na2SO4
Anilinen-Heptane
38
[32]
1997
I
Isatoic anhydride AcCN/Benzene
54%
o-Toluidine Activated C
Acetylating agent TsOH/NaHCO3
  Pet. Ether
39
[35]
1997
I
2-Amino-(N-o-tolyl)-
benzamide
Halogenated
Trialkylsilane
-
Acetylating agent Base

a. Target 4(3H)-quinazolinone(s) reported in reference
following roman numerals as designated in Table 1.


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