Synthesis of deuterium labeled standards of 1-benzylpiperazine, fenetylline, nicocodeine and nicomorphine

Article abstract of DOI:10.1002/jccs.200800099

Increasingly abused, 1-benzylpiperazine (BZP), fenetylline, nicocodeine and nicomorphine are central nervous system stimulants with neurotoxic properties. In recent years, many controlled substance analogs (designer drugs) with a large variety of structures have reached illegal markets, making their identification difficult. This work studies the synthesis of BZP-d₇, fenetylline-d₄, nicocodeine-d₄ and nicomorphine-d ₈, as internal standards for use in gas chromatography-mass spectrometry (GC-MS) analysis for identification of these controlled substances.

Full text of DOI:10.1002/jccs.200800099

Journal of the Chinese Chemical Society, 2008, 55, 663-667
663
Synthesis of Deuterium Labeled Standards of 1-Benzylpiperazine,
Fenetylline, Nicocodeine and Nicomorphine
Zong-Yi You (
Yu-Yun Wang (
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, R.O.C.
), Yi-Jing Chen (
),
) and Chinpiao Chen* (
)
Increasingly abused, 1-benzylpiperazine (BZP), fenetylline, nicocodeine and nicomorphine are cen-
tral nervous system stimulants with neurotoxic properties. In recent years, many controlled substance
analogs (designer drugs) with a large variety of structures have reached illegal markets, making their iden-
tification difficult. This work studies the synthesis of BZP-d7, fenetylline-d4, nicocodeine-d4 and nicomor-
phine-d8, as internal standards for use in gas chromatography-mass spectrometry (GC-MS) analysis for
identification of these controlled substances.
Keywords: BZP; Fenetylline; Nicocodeine; Nicomorphine; GC-MS.
INTRODUCTION
Unknown drugs are generally detected and identified
drug users are ingesting piperazine analogs, such as 1-ben-
zylpiperazine and 1-(m-trifluoromethylphenyl) piperazine
(TFMPP), that mimic the psychoactive effects of 4-methyl-
enedioxmethylamphetamine. Baumann’s results showed
that BZP/TFMPP and MDMA can evoke monoamine re-
lease; however, a dangerous drug-drug synergism may oc-
cur when piperazines are coadministered at high doses.
Fenetylline3 is on a list of compounds that were considered
by a World Health Organization (WHO) expert committee
in April 1985 for possible international scheduling under
the Convention on Psychotropic Substances. For over 23
years, fenetylline has been administered therapeutically to
hyperkinetic children and in other indications in place of
amphetamines and other central stimulants with high risk
levels. Nicocodeine,22 an opiate derivative developed as a
cough suppressant and analgesic is metabolized in the liver
by demethylation to produce 6-nicotinoylmorphine and
then further metabolized to morphine. Side effects are simi-
lar to those of other opiates, including itching, nausea and
respiratory depression. Nicomorphine,22 the 3,6-dinico-
tinate ester of morphine is a strong opioid agonist analgesic
two to three times as potent as morphine with a side effect
profile similar to that of dihydromorphine, hydromor-
phone, and diamorphine. Nicomorphine is commonly used
in patient-controlled analgesia units. Nicomorphine, the
nicocodeine parent chemical is a cough suppressant. Nico-
morphine’s side effects are similar to those of other opiates
and include itching, nausea and respiratory depression.23
by gas chromatography-mass spectrometry because of the
high sensitivity and capability of this method to separate
organic compounds from complex mixtures. Some abused
drugs, such as 1-benzylpiperazine,1-2 fenetylline,3 nicoco-
deine4 and nicomorphine5 are increasingly abused psycho-
active drugs and have been well documented in the litera-
ture. Widespread consumption of designer drugs has led to
an increased number of reports of abuse and intoxication.
The abuse of psychoactive drugs in the phenethyl-
amine and morphine groups has become an extremely seri-
ous problem in Taiwan in the most recent decade.6-18 Am-
phetamine, its N-methyl homologue methylamphetamine,
and 4-methylenedioxmethylamphetamine (MDMA), are
among those most widely abused by young people. Al-
though 1-benzylpiperazine19 was originally synthesized
by Wellcome Research Laboratories as a potential anti-
helminthic agent, research indicated that 1-benzylpiper-
azine caused a reversal of the effects of tetrabenazine (a do-
pamine-depleting drug) in rats and mice, indicating a po-
tential antidepressant activity. Notably, 1-benzylpiperazine
caused hyperactivity, involuntary head movements and a
reduction in reaction time in shock-avoidance studies,
properties also found in amphetamines.20 Baumann et al.21
reported that 3,4-methylenedioxymethamphetamine is an
illicit drug that stimulates release of serotonin and dopa-
mine from neurons. Recent evidence in rats reveals that
* Corresponding author. Tel: +886-3-8633597; Fax: +886-3-8630475; E-mail: chinpiao@mail.ndhu.edu.tw

664 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
You et al.
Standard samples for controlled drug analysis in Tai-
wan are very difficult to obtain. Many researchers are inter-
ested in the preparation of deuterium-labeled controlled
drugs as internal standards for GC-MS analysis.24-30 This
study describes the synthetic routes to BZP-d7, fenetyl-
line-d4, nicocodeine-d4 and nicomorphine-d8, and presents
relevant characteristic analytical data. The synthetic ap-
proach described herein is potentially applicable to the syn-
thesis of a wide variety of other drugs. No reports exist for
the compounds investigated in this study.
Scheme I
D
D
D
D
N
NH
C6D5CD2Cl
H N
NH
D
D
1
2
D
line (4) in a 51% yield. Throphylline (4) and 1,2-dichloro-
ethane-d4 were refluxed in 2-propanol to give 7-(2-chloro-
ethyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione-d4 (5)
in a 33% yield. Fenetylline-d4 (7) was prepared by heating
compound 5 with 1-methyl-2-phenyl-ethylamine (6).
Scheme III presents the preparation of nicocodeine-
d4 (10) and nicomorphine-d8 (11).41 Codeine 8 and mor-
phine 9 were treated with nicotinoyl-d4 chloride (12) to
give the corresponding nicocodeine-d4 (10) and nicomor-
phine-d8 (11).
RESULTS AND DISCUSSION
1-Benzylpiperazine,31-36 fenetylline,37-39 nicoco-
deine40-41 and nicomorphine42 were readily prepared using
various synthetic routes. Preparation of BZP-d7, fenetyl-
line-d4, nicocodeine-d4 and nicomorphine-d8 has not been
described previously. Scheme I presents the general syn-
thetic scheme for preparing 1-benzylpiperazine-d7 (2).32
The reaction between piperazine (1) and benzyl chloride-d7
gave 1-benzylpiperazine-d7 (2) in a 99% yield.
In conclusion, this study demonstrates the syntheses
of BZP-d7, fenetylline-d4, nicocodeine-d4 and nicomor-
phine-d8. Although the retention times of gas chromatogra-
phy (GC) of labeled and unlabeled compounds vary very
little, quantification by mass spectrometry (MS) with the
selected ion monitoring (SIM) technique enhances the per-
Scheme II presents the preparation of fenetylline-d4
(7).37 The reaction of 5,6-diamino-1,3-dimethyl-1H-pyr-
imidine-2,4-dione (3) and formic acid produced throphyl-
Scheme II
O
O
O
D
N
D
H3C
O
NH2
NH2
H
N
Cl
D
N
H3C
O
H3C
O
ClCD2CD2Cl
N
D
N
+
HCO2H
D
N
N
N
N
N
CH3
CH3
4
CH3
5
3
H2N
O
H
N
D
H3C
N
D
N
6
D
CH3
N
O
N
CH3
7
Scheme III
R1O
R1O
H
O
H
O
H
Me
Me
D
N
N
H
COCl
D
R2O
N
R2O
8: R1 = CH3, R2 = H
9: R1 = R2 = H
10: R1 = CH3, R2 = nicotinyl-d4
11: R1 = R2 = nicotinyl-d4
D
D
12

Deuterium Labeled Fenetylline, Nicocodeine, Nicomorphine
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 665
formance of quantitative analysis. Therefore, deuterium-
labeled compounds possess the potential for use as an inter-
nal standard in GC-MS analysis.
calcd for C11H9D7N2 183.1746; found 183.1756.
Throphylline (4)
Throphylline 4 was obtained by heating a mixture of
dimethyldiaminouracil 3 (4.25 g, 25.0 mmol) and HCOOH
(4.8 mL, 0.13 mol) in an open round flask at 110-140 °C for
2 h. Excess formic acid was removed by boiling at atmo-
spheric pressure, and the red-brown residue was converted
to throphylline 4 by heating at 275-300 °C for 20 min. The
crude product was triturated with ethanol and filtrated to
give a brown solid 4 (2.30 g, 12.8 mmol). Yield: 51%. 1H
NMR (400 MHz, CDCl3, d): 7.86 (s, 1H), 3.66 (s, 3H), 3.49
(s, 3H). 13C NMR (100 MHz, CDCl3, d): 156.2, 151.5,
149.1, 140.4, 106.9, 30.3, 28.5. IR (thin film): 3447, 3120,
3066, 2916, 2853, 1717, 1668 cm-1. MS-EI (m/z): 180 (M+,
100), 151 (7), 95 (44), 68 (33). HRMS-EI (m/z): [M]+ calcd
for C7H8O2N4, 180.0647, found, 180.0642.
EXPERIMENTAL SECTION
General Chemical Procedures
1H NMR spectra were acquired at 300 and 400 MHz
(indicated in each case), and 13C NMR were acquired at
75.5 and 100 MHz on a Bruker NMR spectrometer. Chemi-
cal shifts (d) are reported in ppm relative to CHCl3 (7.26
and 77.0 ppm). Mass spectra (MS) and high resolution
mass spectra (HRMS) were determined on a Finnigan/
Thermo Quest MAT 95XL mass spectrometer. Infrared
spectra were recorded using a JASCO FT/IR 410 spectrom-
eter. Dichloromethane and pyridine were distilled from cal-
cium hydride. Flash column chromatography was per-
formed using MN silica gel 60 (70-230 mesh) or basic
Al2O3 which were purchased from Macherey-Nagel.
All reactions were initially optimized using unlabeled
compounds.
7-(2-Chloro-ethyl)-1,3-dimethyl-3,7-dihydro-purine-
2,6-dione-d4 (5)
To a solution of theophylline 4 (0.55 g, 3.1 mmol) and
sodium hydroxide (0.12 g) in water (4 mL) was added a so-
lution of 1,2-dichloroethane-d4 (2.50 g, 24.3 mmol, isotope
purity, D4, 99%, Cambridge Isotope Laboratories) in
2-propanol (6.0 mL). After refluxing at 80-90 ºC for 18 h,
the solvent was evaporated under reduced pressure, and the
solid was filtered out and discarded. The aqueous layer was
extracted 3 times with chloroform, and combined organic
layers were dried over anhydrous sodium sulfate. Filtration
and concentration yielded a residue, which was purified by
flash column chromatography using silica gel as the sta-
tionary phase and ethyl acetate-hexane (1:1) as the mobile
phase to produce compound 5 (0.24 g, 1.0 mmol). Yield:
33%. 1H NMR (400 MHz, CDCl3, d): 7.63 (s, 1H), 3.59 (s,
3H), 3.39 (s, 3H). 13C NMR (100 MHz, CDCl3, d): 160.7,
155.3, 151.6, 149.4, 142.1, 106.4, 29.8, 28.0. IR (thin
film): 3105, 2953, 2359, 2284, 1704, 1660, 1602, 1546,
1471, 1453, 1428, 1348, 1287, 1241, 1197, 1086 cm-1.
MS-EI (m/z): 248 (M+2, 27), 246 (M+, 100), 211 (47), 181
(53), 96 (42), 67 (27). HRMS-EI (m/z): [M]+ calcd for
C9H7D4ClO2N4, 246.0818, found, 246.0829.
1-Benzylpiperazine-d7.HCl (2)
A solution of piperazine hexahydrate (1.46 g, 7.5
mmol) in absolute ethanol (3.0 mL) was warmed at 65 °C,
and piperazine dihydrochloride monohydrate (1.33 g, 7.5
mmol) was added. After warming in a bath to 65 °C, benzyl
chloride-d7 (1.00 g, 7.5 mmol, isotope purity, D7, 98%,
Cambridge Isotope Laboratories) was added during 5 min
of vigorous stirring. The separation of white needles was
almost immediate. The solution was stirred for an addi-
tional 25 min at 65 °C and then cooled in an ice bath with-
out stirring for about 30 min. The crystals of piperazine
dihydrochloride monohydrate were collected by filtration
and then washed with ice-cold absolute ethanol. The com-
bined filtrate and washings from the piperazine dihydro-
chloride were cooled in an ice bath and treated with 25 mL
absolute ethanol saturated at 0 °C with dry hydrogen chlo-
ride. After the solution was well mixed, it was cooled for
10-15 min in an ice bath. The precipitated white plates of
1-benzylpiperazine dihydrochloride were collected by fil-
tration, washed with dry benzene, and dried to give the
product 2 (1.90 g, 7.4 mmol). Yield: 99%. mp: 277-280 °C.
1H NMR (300 MHz, D2O, d): 3.47 (s, 8H). 13C NMR (75
MHz, D2O, d): 131.2-130.1 (m), 129.3-128.6 (m), 127.1,
60.4-60.0 (m), 47.8, 40.7. IR (thin film): 3448, 2896, 2768,
2520, 1630, 1559, 1420, 1301, 1192, 1082, 941, 578, 540
cm-1. MS-EI (m/z): 183 (M+, 27), 152 (3), 141 (71), 127 (4),
98 (100), 85 (13), 70 (10), 56 (20). HRMS-EI (m/z): [M+]
Fenetylline-d4 (7)
A mixture of 7-(3-chloroethyl)-3,7-dihydro-1,3-di-
methyl-1H-purine-2,6-dione-d4 5 (0.22 mg, 0.9 mmol) and
1-methyl-2-phenyl-ethylamine 6 (0.49 g, 3.6 mmol) was
heated at 100 °C for 17 h. After cooling to room tempera-
ture, the saturated aqueous solution of sodium bicarbonate
was added to basify the reaction mixture to a pH of 8. The
aqueous phase was extracted with dichloromethane, and

666 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
You et al.
the organic phase was dried over anhydrous sodium sul-
fate. Filtration and concentration yielded a residue, which
was purified by flash column chromatography using silica
gel as the stationary phase and ethyl acetate as the mobile
phase to produce compound 7 (0.15 g, 0.4 mmol). Yield:
48%. 1H NMR (400 MHz, CDCl3, d): 7.45 (s, 1H), 7.25-
7.17 (m, 3H), 7.09-7.07 (m, 2H), 3.58 (s, 3H), 3.39 (s, 3H),
2.89-2.84 (m, 2H), 2.61-2.57 (m, 1H), 1.04-1.03 (d, J = 6.2
Hz, 3H). 13C NMR (100 MHz, CDCl3, d): 155.2, 151.7,
148.9, 141.7, 139.0, 129.1, 128.3, 126.2, 106.7, 54.3, 43.5,
29.7, 28.0, 20.4. IR (thin film): 3420, 2963, 1704, 1659,
1546, 1453, 1349, 1290, 1235, 1184, 1020 cm-1. MS-FAB
(m/z): 347 (M+ + 2, 55), 345 (M+, 18), 254 (39), 228 (17),
211 (25), 181 (22), 166 (24), 119 (38), 105 (37), 91 (60), 77
(32), 69 (87), 58 (98), 56 (100). HRMS-EI (m/z): [M+]
calcd for C18H19D4N5O2, 345.2099; found 345.2098.
Nicocodeine-d4 (10)
found, 408.1983.
Nicomorphine-d8 (11)
A solution of nicotinic acid-d4 (1.02 g, 8.0 mmol,
prepared from nicotinic acid ethyl ester, isotope purity,
2,4,5,6-D4, 98%, Cambridge Isotope Laboratories) in thio-
nyl chloride (5.0 mL) was refluxed for 2 h, and excess thio-
nyl chloride was removed by distillation to yield nicotinoyl
chloride-d4. To a solution of morphine (1.10 g, 3.8 mmol)
and pyridine (1.2 mL) in dichloromethane (10.0 mL) was
added a solution of nicotinoyl chloride-d4 (8.0 mmol) in di-
chloromethane (15.0 mL). After stirring at room tempera-
ture for 15 h, an additional solution of nicotinoyl chloride-
d4 (8.0 mmol) in dichloromethane (15.0 mL) was added.
After stirring at room temperature for 15 h, the reaction so-
lution was basified by adding a saturated aqueous solution
of sodium bicarbonate. The aqueous phase was extracted
with dichloromethane, and the combined organic solution
was dried over anhydrous magnesium sulfate. Filtration
and concentration yielded a residue, which was purified by
flash column chromatography using silica gel as the sta-
tionary phase and dichloromethane-ethyl acetate (1:9, 1:4)
as the mobile phase producing compound 11 (0.60 g, 1.1
A solution of nicotinic acid-d4 (1.10 g, 8.0 mmol,
prepared from nicotinic acid ethyl ester, isotope purity,
2,4,5,6-D4, 98%, Cambridge Isotope Laboratories) in thio-
nyl chloride (5.0 mL) was refluxed for 2 h, and excess thio-
nyl chloride was removed by distillation to yield nicotinoyl
chloride-d4. A solution of nicotinoyl chloride-d4 in dichlo-
romethane (15.0 mL) was added to a solution of codeine
(1.20 g, 4.0 mmol) and pyridine (1.2 mL) in dichloro-
methane (10.0 mL). After stirring at room temperature for
15 h, the reaction solution was basified by adding a satu-
rated aqueous solution of sodium bicarbonate. The aqueous
phase was extracted with dichloromethane, and the com-
bined organic solution was dried over anhydrous magne-
sium sulfate. Filtration and concentration yielded a residue,
which was purified by flash column chromatography using
Al2O3 as the stationary phase and ethyl acetate-hexane
(1:4, 2:3) as the mobile phase to produce compound 10
1
mmol). Yield: 30%. mp: 174.3-175.2 °C. H NMR (400
MHz, CDCl3, d): 6.90 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2
Hz, 1H), 5.79 (d, J = 9.8 Hz, 1H), 5.57 (d, J = 7.4 Hz, 1H),
5.28 (d, J = 6.8 Hz, 1H), 3.44 (s, 1H), 3.13 (d, J = 18.8 Hz,
1H), 2.86 (s, 1H), 2.73 (d, J = 20.0 Hz, 1H), 2.46 (s, 3H),
2.42-2.37 (m, 2H), 2.18-2.09 (m, 1H), 1.96 (m, 1H). 13C
NMR (100 MHz, CDCl3, d): 164.5, 162.7, 150.6, 132.4,
131.5, 129.5, 128.2, 125.3, 124.7, 121.9, 119.7, 88.4, 67.1,
60.0, 46.6, 42.9, 42.5, 40.2, 34.8, 29.7, 20.9. IR (KBr):
2923, 2893,2290, 2260, 1736, 1718, 1560, 1447, 1250,
1060, 776, 557 cm-1. MS m/z: 503 (M+, 91), 393 (56), 377
(84), 324 (23), 271 (50), 214 (21), 110 (100), 82 (70).
HRMS-EI (m/z): [M]+ calcd for C29H17D8N3O5, 503.2288;
found, 503.2288.
1
(1.65 g, 3.9 mmol). Yield: 97%. mp: 134.7-135.0 °C. H
NMR (400 MHz, CDCl3, d): 6.67 (d, J = 8.2 Hz, 1H), 6.58
(d, J = 8.2 Hz, 1H), 5.78 (d, J = 9.8 Hz, 1H), 5.54 (d, J = 7.4
Hz, 1H), 5.47 (d, J = 6.7 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H),
3.70 (s, 3H), 3.39 (s, 1H), 3.08 (d, J = 18.5 Hz, 1H), 2.81 (s,
1H), 2.60 (d, J = 20.0 Hz, 1H), 2.45 (s, 3H), 2.38-2.34 (m,
2H), 2.08-2.06 (m, 1H), 1.91 (m, 1H). 13C NMR (100 MHz,
CDCl3, d): 164.8, 146.6, 142.2, 130.6, 130.0, 128.0, 126.9,
125.8, 119.4, 114.1, 87.6, 68.7, 59.2, 56.6, 46.8, 43.0, 42.6,
40.6, 35.3, 20.4. IR (KBr): 2918, 2839, 2284, 2260, 1969,
1820, 1723, 1557, 1504, 938, 788, 701 cm-1. MS m/z: 408
(M+, 100), 282 (66), 271 (20), 229 (18), 110 (34), 82 (23).
HRMS-EI (m/z): [M]+ calcd for C24H20D4N2O4, 408.1983;
ACKNOWLEDGEMENT
The authors thank Ms. Hsu, L. M. at the Instruments
Center, National Chung Hsing University, for her help in
obtaining HRMS spectra. We would also like to thank the
National Bureau of Controlled Drugs, Department of Health,
Taiwan, Republic of China, for financially supporting this
research under Contract DOH95-NNB-1001.
Received December 2, 2007.

Deuterium Labeled Fenetylline, Nicocodeine, Nicomorphine
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 667
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