1. No category

Impurities in ilticit amphetamine:a review
By
A. SINNEMA
Laboratory of orgalic chemistry, Department of Chemical rechnology,
Delft University of Technology, Delft, the Netheriands
A. M. A. VERWEIJ
Forensic ScienceLaboratory of the Ministry of Justice, Rijswijk,
the Netherlands
ABSTRACT
The paper reviews the most common synthesisof amphetamineswhich
may
be found in illicit traffic. Emphasis is taid on the detection, isolation
ani
identification of impurities in illicit amphetamines through gas chromatography and thin-layer chromatography. The latter method was
also used
for isolation purposes. Impurities were identified by mass spectral
and
NMR spectroscopicmethods and relevant data are presented.
Introduction
Illegally produced drugs are-frequentlycontaminated,as is
readily shown
by chromatographic analysis. Contaminution, in drugs can
be caused by
laboratory diet, impurities in the starting chemicals,iid"and subsequent
reactions,intermediate products,diluents of tn" drugs and from
handling and
packing of the drugs. Hence two different approaches
can be used for their
identification:
(a) The chromatographicdata can be collected for
comparison purposesin
a classof drugs,the so-called.,signature"method.
(b) contaminants of the main compound may be identified.
In this review, attention will be focused on the latter approach,
since
c h e m i c a l c o mp o u n d s p re s e n t in the fi nal amphetami ne,due' tL
i nadequate
purification of the raw product, will give vaiuable clues
to the method of
synthesis.In this way' suspectedillicit sourcesof amphetamine
can be confirmed
and information provided to the police which may contribute to
tracking down
the illegal production locations.
B*Ll,Nor. 3z(tts )tl
'5"1S.t
al
l7
38
Bulletin on Narcotics, Vol. XXXIII,
No. 3- l98l
Im1;
Synthesisof amphetamine
To date, 23 clandestinelaboratorieshave been discoveredin the Netherlands [1]. The Leuckart reaction (see figure I) [2] was the most frequently
encountered,though in somecasesreductiveaminationof benzylmethyl ketone
was found (figure II). No other synthesessuch as the oxime or the phenylnitropropene routes were encountered.Only once was a methamphetamineproduction location found; in this instancethe substancewas prepared by an almost
professionalprocedure [3], Our findings therefore contrast with those reported
in the United Statesof America, where the accentseemsto be on the production
of methamphetamine [a]. Most of the amphetamine was intended for the
markets of the Federal Republic of Germany and Scandinavia;only a minor
portion of it was sold in the Netherlands.
1 60 t
't4
0(
l2 0{
1 00 (
80
60
40
12
13
W W H
2C
11
10
,:h
#
: :
4
5
9
10
11
12
13
14
&
::::
,ffi,a
#'frt
*
cl^
Ap
ca
;
*
, :.,ir:it:::i),..::::::tt:,:::..
16
17
18
19
14
,..,::,.,,,:
Iil:::,,.:,,.;.,,:::::
4-methyl-5-phenylpyrimidine
5-benzylpyrimidine
2,4-dimethyl-3,5-diphenylpyridine
2,6-dimethyl-3,5-diphenylpyridine
4-methyl-5-phenyl-2-(phenylmethyt)pyridine
2-methyl-3-phenyl-6-(phenytmethyt)pyridine
2,4-dimethyl-3-phenyl-6-(phenytmethyt)pyridine
2-benzyl-2-methyl-5-phenyl-2,3-di hydropyrid -4-one
Compounds4 and 5 were stainedyellow by sprayingthe spots with 1% p-dimethylaminobenzaldehyde
in 50% sulphuricacid and heatingthe plateat 100'Cin a dryingbox.The three
pyridine derivativeswith no o-hydrogenswere stained blue-purple with iodoplatinate
reagent,the other two pyridinesand pyrimidinesbecameyellow or brown. With the latter
r e a g e n t h e p y r i d o n et u r n sr e d d i s h .
FigureI
Thin-layerchromatogramof weaklybasicfractionon Merck precoatedsilicagel 60 F-254
w i t h h e x a n e / e t h e(r5 0 + 5 0 )a s e l u e n t
Cc
YIII, No. 3- t98l
n the Netherrst frequently
nethyl ketone
phenylnitroetamine proI by an almost
rosereported
reproduction
rded for the
.lnly a minor
Impurities in illicit amphetamine: a review
16 000
14 000
12 000
10 000
8 000
6 000
4 000
12
13
2 000
11
10
16
17
18
19
N-acetylamphetamine
N-(p-phenylisopropyl)benzaldimine
N-(p-phenylisopropyl)benzyl
methylketimine
1-oxo-1-phenyl-2-(p-phenylisopropylimino)propane
Chromatographicconditionswere as follows: 2 metre s.s. (0 1/8"\, column packed with
Apiezon/KOH10%/1OYo
on ChromosorbG DCMS(80-100 mesh),oventemperature220"C,
c a r r i e rg a s H e ,f l o w r a t e 1 0m l / m i n .
14
Figure ll
Computer reconstructedchromatogramof the low-pressure,low-temperaturereductive
aminationreactionmixture
The Leucksrt reaction
This reactioncan be describedby the following scheme:
ethylaminox. The three
doplatinate
:h the latter
O.d{H,
benzyl methyl ketone
or ,
H{-NH
1(l)
.2 ----------------
formamide
1(z)
C [-C H -N H {H O
el 60 F-254
+
CH,
N-formylamphetamine
amP hetami ne
= -* ;,.1->
Bulletin on Narcotics, Vol. XXXlll,
No. -l- lq81
i n w h i c h( 1 ) : l U 0 - 1 9 5 " C .
(2 ' l : 9 0 - 1 2 5 " C .
Upon rt
which can st
(3 ), H 2 S O a ,H C I (d i l u t ed).
Reaction conditionscan vary [5], formamide being sometimesreplacedby
ammonium formate [6] or a mixture of ammonia and formic acid [7]. It is clear
that, due to the many possibilitiesfor condensationof benzylmethyl ketone with
formamide, a host of other productscan be expected.This givesrise to a large
nu mb e r o f i m p u ri ti e s i n th e m o re or l esspuri fi ed amphetami ne.In practi ce,
approximately50% amphetamineis recovered[8] ; with the formic acid variant,
recoveryof about 30% is feasible[9]. Methamphetaminepreparedaccordingto
this method contains fewer impurities as the N-methylformamide, used as
starting material, has fewer possibilitiesfor condensationwith benzyl methyl
k eto n e .
Benzyl methyl ketone may be purchasedfrom wholesaledealers,but can
als ob e e a s i l ys y n th e s i z e d[1 0 ].
O
cHf ooH + cH3cooH -#phenylacetic
acid
Impurities in ill,
ketone
benzyl
methyt
benzyl metl
1 ( t ) ,O ( 2 )
i n w h i c h( l )
(2)
(3)
Great C
lytical redur
knowledger
Recoveries
aceticacid
in w h i c h (4 ): 4 5 0 ' C .
(5): ThO2.
Oth e r m e th o d s h a v e a l s o b een reported [11-13]. D i benzyl ketone i s a
side-productof this reaction and its presencein amphetamineis readily understood if benzyl methyl ketone is produced in this way.
The reductive amination ol benzyl methyl ketone
Benzyl methyl ketone can be aminatedas follows Ia]:
o ."J
-CH, +
benzylmethylketone
NH
cat(l),1(2),O(3)
3
amphetamine
Conder
propene. H
give the am
@.'1(l),o(2
reactiont
in which ( I
(2
reaction medium(a).H,
(3
ammonla
in w h i c h (1 ): R a n e y -N i , P t, A l pow der i n the presenceof H gC l 2, ni ckel
plated Zn.
(2): 20-170"C.
(3): 1-130Atm.
(a ): E th a n o l o r m e th a nol .
Reaction conditions reported in the literature differ widely [15- 1f]]. To
date, only low-pressureand low-temperature aminations have been found in
this country. Recoveriesof approximately 90% can be reached if optimized
reactionconditionsare carefullymaintainedand freshlyprepared Raney-nickel
use d[1 9 ]. In th i s c a s eth e re a re f ew er i mpuri ti esthan i n the Leuckart route.
(4
Reacti
been menti
amphetami
We ha
production
chased eas,
Many othe
chemicals,
I
A liter
, - 1 *I 9 U I
Impurities in illicit amphetamine: a review
The oxime ruute
Upon reactionwith hydroxylamine,benzyl methyl ketone givesthe oxime,
which can subsequentlybe hydrogenatedto yield amphetamine[20].
laced by
t is clear
r ne w i th
r a large
rractice,
v ar i a n t,
rr din gto
used as
I m e th yl
but can
't one
benzyl methyl ketone
oxlme
amphetamine
1 ( r ) ,O ( 2 () H
, ytrt
in which(1): 20-170"C.
( 2 \ : 1 - 1 3 0A t m .
(3): Na (amalgamated),Na (absolute ethanol), LiAlH4, or H2 and
Raney-Ni or Ni or Fe or nickel platedZn.
Great differencesare reported in the reactionconditions[2 ] -23]. Electrolytical reduction has also been described[24]. However, this route has to our
knowledgenot been put into practicefor the illegalproduction of amphetamine.
Recoveriesof up to 907o have been reported.
The phenylnitropropene
lne is a
under-
route
Condensationof benzaldehydewith nitroethane yields l-phenyl-2-nitropropene. Hydrogenation of the double bond and reduction of the nitro-group
g i v e th e a mp h e ta mi n e .
@cHo
+ cHicHrNoz-
1 ( r ) , O ( 2 )(,H y r l l
O.*=f;;.*,
amphetamine
reaciion medium(a)
in which(1): 20-100'C.
nine
nickel
(2): 1-80 Atm.
(3 ): L i A l H 4 , H 2 a n d R aney-N i or P d/C .
(a ): C H IO H ; C z H sOH ; H zO/H C OOH ; C H TC OOH /C 2H sOH .
Reaction conditions vary widely I25,,261and electrolyticalreduction has
been mentioned[27]. This synthesishasbeen of importancein Swedenin illegal
a mp h e ta mi n ep ro d u c ti o n[2 81.
Ittl. To
rund in
timized
-nic ke l
rute.
We have given a rather extensive description of some methods for the
production of illegal amphetaminefor which the starting material can be purchasedeasily and in which the chemical operations are not too complicated.
Many other syntheticroutes for amphetamine,often with obscureor intricate
chemicals,are known,l but in this context are of lesserimportance.
' A literature search is available for the interested reader.
42
Bulletin on Narcotics, Vol. XXXIII,
No. -1- 1981
Impu
Detection, isolation and identification of impurities in illicit amphetamine
To obtain impurities in sufficient quantitiesfor analysis,the raw material
was diluted with water and acidified with tartaric acid. This solution was
extracted with ether, and the ether layer was extracted with 4 N hydrochloric
acid. A portion of the hydrochloric acid solution was made alkaline and
extracted with chloroform to give fraction A (weak bases). A quantity of the
Likewise,the
ether layer was evaporatedto give fraction B (neutral substances).
tartaric acid solution was made alkaline and extractedwith chloroform to give
fraction C (strongbases).All three fractionswere investigated,but our attention
was directed mainly to the weak bases.
For a quick survey of the impurities present,thin-layer chromatographyis
the method of choice.Severaleluents,e. g. cyclohexane-benzene-diethylamine
(7 5 : 1 5 : 1 0 ), ' h e x a n e -a cetone(50:50) or (80 :20), hexane-ether(50:50) or
(9 0 : 1 0 ) a n d m e th a n o l -ammoni
a25" /" (99 : 1) w ere tri ed,of w hi ch hexane-ether
(50: 50) gave the best results(seefigure I).
Gas chromatographyon?"/" OV- 17 or l0% 110% Apiezon/KOH columns
in an isothermal (200"C) or better, in a programmed mode (100-250'C,
2"Clmin) was performed (see figure II).
Isolation of the compounds with a purity of better than 95 "/" can be
achievedby repetitivethin-layer chromatographicruns, using a combination of
the above-mentioned eluents. In the literature, a high-performance liquid
chromatographic(HPLC) method for these purposeshas been reported [28].
The isolated compounds were identified by a combination of low- and hight3C NMR spectroscopy
resolutionmassspectrometry,andrH and
[29-34].
None the less,the describedisolation procedure does not alwaysgive the
desired results. The gas chromatograph/massspectrometercombination can
then be used in the low- and the high-resolution mode. Compounds, whose
structureswere tentatively derived from massspectraldata, were synthesized.
In most instancesthe problem of structure elucidation was then solved by
comparison of the chromatographic and the mass spectral data of the synthesizedsubstances
with thosewhosestructuresare to be elucidated[35, 36].
The use of low-resolution mass spectral data alone in structure determination is not recommended.It can easilylead to erroneousresultsbecausethe
massspectraof the variouscompoundscan be very similar.
Impurities found in illicit amphetamine prepared via the various synthetic routes
The impurities found so far in the Leuckart synthesisand the reductive
amination routes are presentedin tables I and 2.
Remarkably few impurities are known of the other two routes. Stromberg
reported [28] the presenceof phenylacetoximein a seizure of amphetamine
preparedby the electrolyticreductionof phenylnitropropene,while Kotera [37]
hasindicated2-methyl-3-phenylaziridineand 2-benzylaziridineas by-products
i n th e re d u c ti o no f p h e n yl acetoxi me
w i th l i thi um al umi ni um hydri de.
-s
,as?H
Eg
eeg?sE?
fliEe
Ie [ericffii?rEeiif
X
\
.\
-a.
t{
I
.rc
Table I
\
Reported impurities in amphetamine synthesized by the Leuckart method
b,
Molecular weight
Nume and structure
Formula
Remarks
Referent'es
46.0
cH202
Formic acid
HCOOH
-t
134.1
GH'oO
B e n z y l m e t h y l k e t o n e ( p h e n y l a c e t o n e ,l - p h e n y l p r o p a n o n e )
a
€
1 6 31.
croHr3NO
N-formylamphetamine
((
\--z/
) > c F tt { H - N H { H O
I
CH,
17 0 . 1
C11H1sN2
4-Methyl-5-phenylpyrimidine
o{)
cld
CH,
170.1
C11H1sN2
4-Benzylpyrimidine
",#
cld
29
\
Table I (continued)
Molecular weight
Formula
Cr.HrrO
Name and structure
References
D i b e n z y l k e t o n e( 1 , 3 - d i p h e n y l a c e t o n e1, , 3 - d i p h e n y l p r o p a n o n e )
-o
OcHtE{",O
2 1 1. 1
crsHrTN
c - B e n z y l p h e n e t h y l a m i n(ed i b e n z y l m e t h y l a m i n e )
@.H-cH{-r-O
NH,
253.2
cr8H23N
Di-(B-phenylisopropyl)amine
@.'
-{H{H
t\
t2140
3
z
\
n
NH
s-
,61/
(J.kHlcH{H,
259.1
cieHrTN
\
x
x
o-.vo
2 , 4 -D i m e t h y l- 3 , , 5- d i p h e n y l p y r i dni e
F
z
6
(^,
I
Cc
\,,\,.,
CreHrrN
2 . 6 - D i m e t h y l - 3 , 5- d i p h e n y l p y r i d i n e
JI
l-r
tY
t\
l.\
lI-
o
\4,
259.1
CreHuN
2 , 6 -D i m e t h y l - 3 . 5- d i p h e n y l p y r i d i n e
:
I
ia
-1 I
q
t
259.1
C1eH17N
4 - M e t h y l - 5- p h e n y l - 2 - ( p h e n y l m e t h y l ) p y r i d i n e
3l
|.:
l ^
t:
lr\
l:.
lc
t<
)z
259.1
C1eH17N
2-Methyl-3-phenyl-6-(phenylmethyl)pyridine
oF."d
2'73.2
C21yH1eN
2 , 4 - D i m e t h y l - 3 - p h e n y l - 6 -p( h e n y l m e t h y )l p y r i d i n e
-)z
\
Table / (continued)
Molecular weight
277.1
Formula
creHreNO
Name and strucrure
Remarks
2 -B e nzyl-2 -m et h yl - 5 - p h e n y l - 2, 3 - d i h yd ro py ri d - 4 - on e
References
30
o
c H2 .
cH,i'l
281.2
creH2.rNO
4l
N,N-di-(B-phenylisopropyl)formamide
cHfH{H3
\
N_CHO
^
z
/
HfH{H3
N o t e : a : s t a r t i n g m a t e r i a l; b : i n t e r m e d i a t e p r o d u c t ; c : p r o d u c l
of side reaction;d:"route
s
specific"impurity.
k
x
\
:
zQ
I
,-.
t=
Molecular
Table 2
I E
low-pressure and low-temperature reductive amination
Reported imPurities in amphetamine synthesizedby
l i ,
v'eight
f ormula
Nttme and slruclure
Remarks
References
ta
l'
lI A
I t
\
\
:
z
:
6
I
*rc
Table 2
\
Reported impurities in amphetamine synthesizedby low-pressure and low-temperature reductive amination
,Volet ular weight
Name and structure
Formula
Remarks
References
c r r Hr 5 N o
N-acetylamphetamine
,6f".?
KJrHtcH-NH{-cH3
223.1
cr6HrTN
N-(B-phenylisopropyl)benzaldimine
rt
/,A.\
t
|
\/cH2-c{H
\3
N
,.A.
/
\Jrc-H
251.2
crsHrN
N - ( p - p h e n y l i s o p r o p y l ) b e n z ym
l ethyl ketimine
@cH.-cfH,
,/
(( )Fcn^-cH{H\z/73
35
Table 2 (continued)
253.2
cr8H2.1N
i:::'""i
.\'ume and stru(ture
["orrrtulu
,\loleculur w'eight
1 4 l4 0
a
D i - ( B - p h e n y l i s o p r o p y)la m in e
.rfl*",
NH
,
\/
(Jh.HtcH{H3
265.2
cr8HreNO
I - O x o - 1- p h e n y l -2 - ( B - p h e n y l i s o p r o p y l i m i n o ) p r o p a n e
H
SJrcH2-c({H3
z
-
N
/
-c-cH,
,4.?
V/-c
268.2
C1sH21yO2
a
?
s
1 A
J+
2 , 4 - D i h y d r o x y -l , - 5 - d i p h e n y l - 4 - m e t h y l p e n t e In e -
OH
\
X
QH
l_6\
I
ar.
((
))-cn=c{Htf{Hd/
-c", \-
v
X
z.
I
cc
N o t e ; a : i n t e r m e d i a t ep r o d u c t ; b = p r o d u c t i t f s i d e r e a c t i o n .
?
)FtO
i+
Fo
?
-J
=
-j
=
3'rA
'r50
:z
-lo
l-
t'J
-
-
i5'J x= I : ;'€ g s s r ; = - - SFi
tJ
N)
f.J
N)
-
iJ
i!
:-
-'rJ
'rJ
Nr
f'J
N)
t'J
-
i-l
*
t'J
P
P
X
N)
?
+
B
C=
=3
\t
Art
v
t!
Q.Q
OC)
-r f,.=
.,9'=
1r
\to. -l - l<lUI
Impurities in illicit amphetumine: u review
Mass spectrometric and 2H NMR spectroscopicdata
In table 3 the massspectralfragmentationsare given for the compounds
describedin tables 1 and 2 (mle of the most intensefragmentsare in decreasing
order of intensity).
In table 4, I H NMR spectroscopicdata are given for most of the impurities
i n ta b l e s 1 a n d 2 .
Table 3
Mass spectral data of impurities (m/e of most intense fragments in decreasing
order of intensitv)
Fragments
Molecular weight
t\
-/
lnl
E
).q
tr
/{
1(\{
r
JI
J
ll
r
(J
I
^\-
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
46.0
r34.1
16 3 . 1
17 0 . 1
17 0 . 1
210.1
2lt.l
253.2
259.1
259.1
259.1
259.1
273.2
27'7.1
281.2
117.1
223.1
251.2
265.2
268.2'
4 6 - 2 9 - 4 5 - l t i - 2 8 - 4 1- t 7 92- 43- 6-5- 77- 899l-13472- 44-ll89l- 651 7 0- 1 6 9- t 0 2 - l 1 5 - l 1 6 - l l t - - s l1 6 9 - 1 7 0 - 9 l - 1 1 5- 1 4 2 - 6 - s- 1 1 6 92- 63- lt99l65- 39-ll9t20- 9r- 42- 77-tO3- 65- 5l65- 4t9t- 44-162-tt9259 - 260 - 244 - I 1-5- 2t5 - 202 - I 16 2s9 - 260 - 115 - 244 - r0l - 202 - 2ts 9 12-58-259-243-244-260- lls258 - 259 - 180- 244 - 260 - t82 - 1l-5272-273- 258- 55- 57- 7t- 191 8 6 - 9 l - 1 5 8 - 1 4 3- 1 8 7- 6 5 - l l - 5 9 1- 1 9 0 - l 1 9 1244- tt6-119- 9l- 65- 58- 5l 132- l0-5- 9l- 7',7- 6-5- 5l - 399l-l19-1604t- 6-s- 7T- 399t - ll9- 43- 105- 77-160- 4t 9 l - l - 5 9 - l 3 l - 6 5 - l 1 5 - 5 1- 3 9 -
References
42
4
4
29
29
+
J-)
34
3l
3l
3t
3l
J/.
30
4l
36
35
3-s
36
1 A
-)+
L
Note: B:
base peak. In most cases70 eV electron impact spectra are given.
" The actual massspectrum is of the dehydratcd compound.
a
Table 4
tH NMR spectroscopic data
and assignments for most of the impurities
-
E
Solvent
N M R data and assignment (6-vulues, ppm)
46.0
I34.1
16 3 . 1
DtO
CCU
CCl4
17 0 . 1
CDCII
170.1
CDCIr
8.22 (s): HCOOH
2 . 0 0 ( s , 3 H ) :C H r ; 3 . 5 6 ( s . 2 H ) :C H z ; - 7 . 2 ( 5 H ) : p h e n y l
l . 0 U ( d , 3 H ,J : 7 H z ) : C H t ; 2 . 7 0 ( m , 2 H ) : C H 2 ; 4 . 2 0 ( m , l H ) :
C H ; 1 . 1 2 ( 5 H ) : p h e n y l ; 7 . 5 7 ( s s , 1 H ) :N H " ; 7 . t t - 5( s , l H ) :
HCONH
2.5 (s,3H): CH..t7.4 (5H): phenyl; ft.6 (s,lH): 6-H; 9.1
( s , l H ) :2 - H
4 . 0 ( s , 2 H ) :C H 2 ; 7 . 0( d , l H , J : 6 H z ) : 5 - H ; 7 . 2( 5 H ) : p h e n y l ;
t t . 6( d , l H , J : 6 H z ) : 6 - H ; 9 . 2 ( s , l H ) : 2 - H
Molecularweight
ll
";
?
Referenc'es
29
29
Bulletin on Narcotics,Vol. XXXIII,
No. -l- l98l
Table 4 (continued)
llole< ulur wcight
Solt'ent
2r0.I
2 1 1. l
CCl4
DrO
259.1
259.1
259.1
259.l
273.2
277.1
281.2
269.2h
(6-r'ulues,ppm)
N M R datu and us.signment
3 . 5 3( s , 4 H ) : 2 C H 2 ;.70 - 7 . 5 ( l 0 H ) : 2 p h e n y l
; . 0 - 4 . 0( m , l H ) : C H 7 . 3 7( l 0 H ) :
3.003
, . 0 2( 4 H ) :2 C H 2 3
2 phenyl
C D C I 3 1 . 9 0( s , 3 H )4: - C H r ; 2 . 2 7( s , 3 H )2: - C H ; ; 7 . 0 - 7 . 5( 1 0 H ) :
2 p h e n y l8; . 2 2( s , 1 H )6: - H
: C H r ;7 . 3 5( q r - s ,I1H ) : 4 - H + 2 p h e n y l
C D C I 3 2 . 5 3( s , 6 H ) 2
C D C I . T2 . 1 7( s , 3 H )C: H . r ; 4 . 1(3s , 2 H )C: H z ; 6 . 9 (7s , l H ) : 3 - H ; 7 . 3
( l 0 H ) : 2 p h e n y l8; . 3 5( s , l H ) :6 - H
C D C I 1 2 . 5 0( s , 3 H ) :C H r ; 4 . 1 7( s , 2 H ) :C H z ;6 . 9 0( d , 1 H , , / : 8 H z ) :
5 - H ; 7 . 3( d , lH , " / : 8 H z ) :4 - H
C D C I I 1 . 9 2( s , 3 H ) : 4 - C H r2i . 2 5( s , 3 H ) : 2 - C H r ; 4 . 1( s2 , 2 H )C: H 2 ;
6 . 7 8( s , l H ) : 5 - H ; 7 . 0 - ' 1 .(5l 0 H ) :2 p h e n y l
CDCI3 1.20(s,3H):CHr; 2.50(s,2H):CH2;2.83(AB,2H,J:l2Hz):
c y c l . - C H 25
; . 6 3( d , l H , l = 7 H z ) : N H ; 7 . 2 ( l l H ) : 6 - H + 2
phenyl
: H r i 2 . 5 5 . 2 . 8 3 , 2 . 8( 48 H ) :
: H : ; 1 . 2 1( d , 3 H ) C
C D C I : 1 . 1 0( d , 3 H ) C
2CHz;3.49,3.93(2H) : 2CH; 6.9- 7.5 ( I 0H) : 2 phenyl;8.22
( s , l H ) :H C O N :
: H r ;2 . 9 0( s , 2 H )3: - C H 2 ;3 . 0 5( s , 2 H )5: - C H z ;
C D C h 1 . 3 2( s , 3 H )C
3 . 7 3 ( s , 2 H ) :1 - C H z ; - 4 . 9 ( b s ) :O H ; 7 . 0 - 7 . 4 ( l O H ) : 2
phenyl
ReJerences
4
39
3l
3l
3l
32
32
4l
34
Nore:s=singlet;d=doublet;m=multiplet;ss=doublesinglet;r1r-s=pseudo-singlet;bs:broadsinglet;
AB=a proton pair for which the difference in chemical shift is of the same order as the coupling constant;
,/ : coupling constant.
'
A double singlct, with unequal intensities,is observed from two isomers due to restricted rotation about
the C-N hond.
n The
data are for the keto-form. which dominates in solution.
Conclusions
Among the impurities identified so far in illicit amphetamineproduced by
the Leuckart synthesis, some compounds such as N-formylamphetamine,
4-methyl-5-phenylpyrimidine and 4-benzylpyrimidinecan be designated as
"route specific" [38], i.e. by their presencethey give direct evidence of the
synthesisused. In particular 4-methyl-5-phenylpyrimidineis extremely well
suitedfor this purposeaswe found it presentin high quantitiesin nearly all illicit
amphetamines analysed. Thin-layer chromatography, preceded by the
extractiondescribedabove,is the method of choice at this point in the analysis.
The use of the Leuckart route can then further be establishedby looking for
some of the other impurities mentioned in tables 1 and 2. This should be done
by the gas chromatographic/massspectrometricmethod in the low-resolution
mode, making use of the massspectraldata in table 3. The variation in mass
spectraldata between classesof compoundsis specificenough to ascertainthe
class.Within a class the various compounds must first be isolated and then
structureelucidationis straightforwardby NMR spectroscopicmethods.
lmpuritt
TI
someu
2,4-d|l
ongrni
impuri
propyl
known
propyl
all am1
N-(0-r
am ine,
isoprol
of am p
N-(0-r
substar
simulti
propyl
capilla
betwet
and m
involvr
higher
amphe
D
phenyl
TI
A.B.F
mental
l.H
2.R
D
3.A
ir
N
I
II, No.3- 1981
Relerences
H):
4
39
H):
3l
7.3
3l
3l
lz.):
32
Hz;
JZ
lz):
+2
30
H);
.22
4l
H:l
:2
34
. = broad singlet;
upling constant;
'd rotation about
5I
The art of low-pressure, low-temperature reductive amination seems
somewhatunderdevelopedas comparedwith the Leuckart route. The impurity,
2 ,4 -d i h y d ro x y -1 ,5 -d iphenyl -4-methyl pentene-1,
w as i nci dental l y found to
originate in our opinion from imperfect chemical handling. Of the other five
impurities in table 2, Haskelberg [14] already mentioned di-(B-phenylisopropyl)amine as an impurity in reductive amination (the compound is already
known from the Leuckart route). The intermediate product N-(B-phenylisopropyl)benzylmethyl ketimine is, to our knowledge,presentin fair quantitiesin
all amphetaminesproduced by this method. It was pointed out, however, that
N-(p-phenylisopropyl)benzylmethyl ketimine together with N-acetylampheta m i n e , N -(B -p h e n y l i sopropyl )benzal di mi and
ne 1-oxo-1-phenyl -2-(B -phenyl isopropylimino)propanecan also be obtained by refluxing equivalent amounts
of amphetamineand benzylmethyl ketone in benzene[34,35]. The presenceof
N-(B-phenylisopropyl)benzylmethyl ketimine on its own by no means gives
substantialevidence of the reductive amination route to amphetamine.The
simultaneouspresenceof di-(B-phenylisopropyl)amineand N-(B-phenylisopropyl)benzyl methyl ketimine separated by gas chromatography using
capillarycolumnsand then identified by massspectroscopyusingthe difference
between their molecular ions mle 253 and m/e 25 1 and the abundant mle 162
and m/e 160 ions, leads us to concludethat a hydrogenationstep at least was
involved. This evidenceof organic impurities may possiblybe supported by a
higher level of inorganic impurities from the catalystused in the production of
a mp h e ta mi n e .
Due to scarcityof publisheddata no further remarks about the oxime and
phenylnitropropeneroute are given here.
Ackrun,ledgement
rroducedby
r phe ta mi n e ,
signated as
ence of the
-emely well
rrly all illicit
:d by th e
he an a l ysi s .
looking for
rld b e d o n e
-resolution
ion in mass
scertainthe
d and then
rods.
The authorsthank Dr. A. M. van der Ark for stimulatingdiscussions
and Ing.
A. B. E. Theeuwen
andMr. J. M. vanderToornfor theirskilfulassistance
in the experimentalpartof thiswork.
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