Research Article

Received 13 August 2007, Revised 8 November 2007, Accepted 8 November 2007 Published online 14 January 2008 in Wiley Interscience

(www.interscience.wiley.com) DOI: 10.1002/jlcr.1484

Synthesis of deuterium-labeled zaleplon-d5 as

an internal standard
Ajam C . Shaikh, and Chinpiao Chen
Zaleplon is licensed for the short-term treatment of insomnia. Excessive usage causes side effects; hence, the drug is
controlled. Identifying zaleplon in a drug abuser requires an isotope-labeled internal standard. This work presents a
synthesis of stable isotope-labeled internal standard for zaleplon, zaleplon-d5, by a five-step synthetic sequence.

Keywords: insomnia; abused drug; zaleplon; zaleplon-d5; internal standard

Introduction are required to ensure accurate analyses of controlled substance

and related compounds. To our knowledge synthesis of stable-
Drugs of abuse are typically detected and identified by gas labeled standard for analyzing zaleplon has not been published.
chromatography-mass spectrometry (GC-MS) because of the Accordingly, an approach for synthesizing such a standard is
high sensitivity of this method and its ability to separate described herein.
complex mixtures of organic compounds.1–4 Standard samples
used for analyzing controlled drugs in Taiwan are very difficult Results and discussion
to obtain. The use of deuterium-labeled controlled drugs as
internal standards for use in GC-MS analysis is well documen- Our first route to zaleplon-d5 is shown in Scheme 1. Initially, 30 -
ted.5–9 This work describes a synthesis of zaleplon-d5, which can nitroacetophenone 1 was treated with N,N-dimethylformamide
serve as an internal standard for the identification of zaleplon by dimethylacetal under reflux to yield the intermediate, enamide
GC-MS analysis. 2.29,30 Another key intermediate, 5-amino-1H-pyrazole-4-carbo-
Zaleplon is a pyrazolopyrimidine sedative–hypnotic10,11 agent nitrile (4) was obtained by refluxing ethoxymethylenemalononi-
for the treatment of insomnia.11 Other members of this class trile (3) and hydrazine hydrate in ethanol.31 In the following step,
include zopiclone, zolpidem and eszopiclone.12 Zaleplon is a compounds 4 and 2 underwent cyclization under mild acidic
short acting benzodiazepine-like hypnotic drug, which is condition at reflux to yield 7-(3-nitro-phenyl)-pyrazolo[1,5-a]-
licensed for the short-term treatment of patients with insomnia pyrimidine-3-carbonitrile (5).29 An efficient reduction of 5 using
who experience early morning awakening. It does not increase 10% Pd/C catalyst at an H2 pressure of 60 psi gave
sleep duration, unlike other hypnotics.13 7-(3-amino-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (6).
Investigations into the action of zaleplon have demonstrated The 3-amino phenyl pyrazolopyrimidine 6 was treated with an
that it selectively binds to the benzodiazepine type 1 site on the acetic anhydride and pyridine to produce acetamide 7.32
c-aminobutyric acid subtype A (GABAA) receptor/chloride-ion Introduction of the isotopic label was attempted by treating
channel complex.14,15 It has a short action onset time, peak acetamide 7 with ethyl iodide-d5 in the presence of sodium
plasma concentration time and elimination half-life of approxi- hydride, under an inert atmosphere at 501C. Unfortunately, the
mately 1 h each.16 Zaleplon is effective in treating insomnia with yield of zaleplon-d5 so obtained was insignificant. Various
fewer residual central nervous system or ‘hangover’ effects than alternative conditions were tried but the maximum yield
are observed in patients on other drugs of the benzodiazepine obtained was only 20%.33 The purification of zaleplon-d5 was
group.17–19 These advantages have resulted in an enormous also problematical as zaleplon-d5 could not be successfully
increase in the use of zaleplon worldwide. crystallized and elution from a silica column was difficult.
Zaleplon is reportedly a habit-forming drug, meaning that Therefore, this route was abandoned.
addiction may occur. Stopping this medication abruptly after
prolonged or frequent use may cause major withdrawal effects,
such as mood change, anxiety and restlessness.20 Accompany-
ing side-effects include hallucination,10 severe confusion,21
daytime drowsiness,22 dizziness,23 headache,24,25 vomiting20
and others. Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974,
Zaleplon is regulated as a controlled drug in some countries Taiwan, Republic of China
such as the United States,26 because an increasing number of *Correspondence to: Chinpiao Chen, Department of Chemistry, National Dong
investigations have reported abuse and intoxication.10,27,28 Hwa University, Soufeng, Hualien 974, Taiwan, Republic of China.
High-purity standards, including isotopically labeled analogs, E-mail: chinpiao@mail.ndhu.edu.tw
72

J. Label Compd. Radiopharm 2008, 51 72–76 Copyright r 2008 John Wiley & Sons, Ltd.
A. C. Shaikh and C. Chen

O
O
Me
(MeO)2CHN(Me)2
NMe2
reflux, 19 h, 87%
NO2
NO2
NO2
AcOH, reflux
1 2
12 h, 87% N N
EtO CN NC
N2H4.H2O, EtOH N
N CN
H CN reflux, 3.5 h, 57% N 5
H2N H
3
4

C2D5
NH2 NHAc NAc

10% Pd/C, H2 (60 psi) Ac2O, pyridine EtI-d5, NaH, THF

EtOAc, rt, 9 h, 82% rt, 20 h, 88% 50°C, 60 h, 20%

N N N N N N

N N N
CN CN CN
6 7 8

Scheme 1

O
O O
Me
10% Pd/C, H2 (60 psi) Me Ac2O, Pyridine Me (MeO)2CHN(Me)2
EtOAc, rt, 8 h, 92% rt, 1 h, 99% reflux, 14 h, 95%

NO2
NH2 NHAc
1 9 10

NC C2D5
NHAc C2D5 N N Me
NAc N
H2N H 4 O
EtI-d5, NaH, DMF
0°C to rt, 1 h, 96% aq. AcOH, 50°C
O NMe2 2 h, 85% N N
O NMe2
N
11 CN
12 8

Scheme 2

Dusza et al. described another route that satisfied our yield Experimental
requirements, shown in Scheme 2.34 Their synthesis started from
compound 10, which is not commercially available. Therefore, General
the route was modified to start with compound 1, which is
readily available and inexpensive. 30 -Nitroacetophenone 1 was 1
H NMR spectra were acquired at 300 and 400 MHz (indicated in
reduced to 30 -aminoacetophenone 935 and subsequent acyla- each case), and 13C NMR were acquired at 75.5 MHz on a Bruker
tion yielded the acetamide 10, which in turn was treated with NMR spectrometer. Chemical shifts (d) are reported in ppm
N,N-dimethylformamide dimethylacetal to produce enamide 11. relative to CHCl3 (7.26 and 77.0 ppm). Mass spectra (MS) and
Enamide 11 was alkylated using ethyl iodide-d5 and sodium high-resolution mass spectra (HRMS) were determined on a
hydride as base at room temperature to yield the N-ethylated Finnigan/Thermo Quest MAT 95XL mass spectrometer. Infrared
enamide 12.34 In the final step, N-ethylenamide 12 was coupled spectra were recorded using a JASCO FT/IR 410 spectrometer.
with 5-aminopyrazole 4 in aqueous acid at 501C to produce All reactions were performed in anhydrous solvents. Tetrahy-
zaleplon-d5 8 in 85% yield.36 Further purification by recrystalliza- drofuran and diethyl ether were distilled from sodium-benzo-
tion of the crude product from 30% aqueous acetic acid yielded phenone in argon. Benzene and N,N-dimethylformamide were
colorless crystals of zaleplon-d5 8.37 distilled from calcium hydride. All air-sensitive reactions were
In summary, this work presents an elegant route to zaleplon- performed in dry glassware under nitrogen using a standard
d5, an internal standard for zaleplon analysis. This synthesis glovebox. Flash column chromatography was performed using
makes way for the quantitative detection of zaleplon in drug MN silica gel 60 (70-230 mesh) or basic Al2O3, which were
abusers. purchased from Macherey-Nagel.
73

J. Label Compd. Radiopharm 2008, 51 72–76 Copyright r 2008 John Wiley & Sons, Ltd. www.jlcr.org
 A. C. Shaikh and C. Chen

All reactions were initially optimized using unlabeled com- (55), 208 (5), 117 (6), 91 (4), 65 (5). HRMS-EI (m/z): [M]1 calcd. for
pounds. C13H9N5, 235.0858; found 235.0862.
Synthesis of 3-dimethylamino-1-(3-nitro-phenyl)-2-propen-1-one Synthesis of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phe-
(2): A mixture of 30 -nitroacetophenone (1) (5.00 g, 30.2 mmol) nyl]-acetamide (7): To compound (6) (0.22 g, 0.97 mmol) acetic
and N,N-dimethylformamide dimethylacetal (4.00 mL, anhydride (2.28 mL, 24.1 mmol) and pyridine (2.28 mL) were
30.2 mmol) was heated at reflux for 19 h. The reaction mixture successively added. The reaction mixture was stirred at room
was evaporated to dryness in vacuo and the residue suspended temperature for 20 h. The mixture was then poured into stirred
in n-heptane (30 mL). The solid obtained was isolated by water (35 mL). The solid formed was collected by filtration and
filtration to give 2 (5.82 g, 26.4 mmol). Yield: 88%. Compound purified by column chromatography using silica gel as the
2 was used in the subsequent reaction without further stationary phase and 50% ethyl acetate–hexane as the mobile
purification. phase yielding 7 as colourless crystals (0.24 g, 0.85 mmol). Yield:
Synthesis of 5-amino-1H-pyrazole-4-carbonitrile (4): A mixture 88%. M.p.: 254–2551C. 1H NMR (300 MHz, DMSO-d6, d): 10.22
of 3 (4.00 g, 32.7 mmol) and 80% hydrazine hydrate (1.49 mL, (s, 1H), 8.82 (d, J = 4.5 Hz, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 7.81
30.7 mmol) was refluxed in EtOH (20 mL) for 3.5 h. The solvent (d, J = 8.5 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 4.5 Hz, 1H),
was removed in vacuo. The resulted solid was purified by 2.16 (s, 3H). 13C NMR (75.5 MHz, DMSO-d6, d): 169.2, 154.2, 151.5,
column chromatography using silica gel as the stationary phase 148.0, 147.7, 139.9, 130.3, 129.6, 124.8, 122.5, 120.4, 113.9, 111.1,
and 45% ethyl acetate–hexane as the mobile phase, yielding 4 81.8, 24.4. IR (KBr, thin film): 3432, 2916, 2232, 1542, 440 cm
1.
as a yellow solid (2.04 g, 18.9 mmol). Yield: 58%. M.p.: 168–1691C, MS-EI (m/z): 277 (M1, 4), 265 (100), 264 (23), 219 (44), 218 (50),
[lit. 167–1691C].31 1H NMR (300 MHz, DMSO-d6, d): 11.98 (br s, 1 174 (18), 135 (15), 57 (21). HRMS-EI (m/z): [M]1 calcd. for
H), 7.57 (br s, 1 H), 6.26 (br s, 2 H). 13C NMR (75.5 MHz, dimethyl C15H11N5O, 277.0964; found 277.0965.
sulfoxide (DMSO)-d6, d): 154.9, 138.9, 115.8, 73.8. IR (KBr, thin Synthesis of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phe-
film): 3416, 3342, 3147, 2958, 1570, 1221, 1034, 716 cm
1. MS-EI nyl]-N–[2H5]-ethyl-acetamide (8): (Scheme 1) A mixture of 7
(m/z): 108 (M1, 100), 79 (10), 54 (15), 53 (26), 52 (22). HRMS-EI (0.50 g, 1.8 mmol) and ethyl iodide-d5 (2.12 mL, 26.5 mmol;
(m/z): [M]1 calcd. for C4H4N4, 108.0436; found 108.0427. isotopic abundance 99%, Cambridge Isotope Laboratories Inc.)
Synthesis of 7-(3-nitro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-car- in dry THF (75 mL) was added under an inert atmosphere to the
bonitrile (5): A mixture of 2 (3.42 g, 15.5 mmol) and 4 (1.50 g, reaction flask that contained sodium hydride (0.81 g, 33.7 mmol).
13.8 mmol) in glacial acetic acid (24 mL) was refluxed for 12 h. This reaction mixture was then stirred at 501C for 60 h. Excess
The reaction mixture was poured into ice water (50 mL) and sodium hydride was then destroyed by adding water (10 mL)
extracted with chloroform (3  50 mL). The organic phase was and the aqueous phase finally extracted with ethyl acetate.
washed using 1 M NaOH (2  50 mL) and brine (50 mL) and dried Collected ethyl acetate fractions were dried over anhydrous
over anhydrous Na2SO4. The solvent was evaporated in vacuo to Na2SO4 and concentrated in vacuo to give a residue, which was
give a residue, which was purified by column chromatography further purified by recrystallization of the product using 30%
using silica gel as the stationary phase and 35% ethyl aqueous acetic acid, yielding 8 as colorless crystals (0.11 g,
acetate–hexane as the mobile phase, furnished 5 as brown 0.35 mmol). Yield: 20%. M.p.: 185–1861C. 1H NMR (300 MHz,
crystals (2.62 g, 9.9 mmol). Yield: 70%. M.p.: 213–2141C. 1H NMR CDCl3, d): 8.79 (d, J = 4.2 Hz, 1 H), 8.42 (s, 1 H), 7.97 (d, J = 8.1 Hz,
(300 MHz, DMSO-d6, d): 8.95 (d, J = 4.2 Hz, 2H), 8.88 (d, J = 2.1 Hz, 1 H), 7.93 (s, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H),
1 H), 8.47 (m, 2 H), 7.94 (t, J = 8.2 Hz, 1 H), 7.72 (t, J = 3.0 Hz, 1 H). 7.20 (d, J = 4.2 Hz, 1 H), 1.9 (s, 3 H). 13C NMR (75.5 MHz, CDCl3, d):
13
C NMR (75.5 MHz, DMSO-d6, d): 154.3, 151.3, 148.0, 147.8, 169.9, 152.7, 151.4, 147.1, 147.0, 143.4, 131.5, 130.9, 130.4, 130.0,
145.7, 136.5, 131.3, 130.8, 126.5, 125.2, 113.7, 111.7, 82.1. IR (KBr, 129.6, 112.7, 110.0, 83.7, 43.6 (m), 23.0, 12.1 (m). IR (KBr, thin
thin film): 3069, 2227, 1608, 1530, 1357, 1272, 839, 741, film): 3055, 2359, 2229, 1615, 1548, 1484, 1392, 1223, 698 cm
1.
728 cm
1. MS-EI (m/z): 265 (M1, 100), 264 (74), 220 (23), 219 MS-EI (m/z): 310 (M1, 55), 268 (50), 251 (18), 250 (100), 234 (4),
(87), 218 (89), 165 (25), 140 (10). HRMS-EI (m/z): [M]1 calcd. for 219 (5), 132 (5). HRMS-EI (m/z): [M]1 calcd. for C17H10D5N5O,
C13H7N5O2, 265.0600; found 265.0609. 310.1585; found 310.1588.
Synthesis of 7-(3-amino-phenyl)-pyrazolo[1,5-a]pyrimidine-3- Synthesis of 1-(3-amino-phenyl)-ethanone (9): 30 -Nitroaceto-
carbonitrile (6): 7-(3-Nitro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-car- phenone (1) (5.00 g, 30.2 mmol) was dissolved in ethyl acetate
bonitrile (5) (0.20 g, 0.75 mmol) was dissolved in ethyl acetate (50 mL) in a pressure vessel and 10% Pd/C (150 mg) was added
(100 mL) in a pressure vessel and 10% Pd/C (40 mg) was added to it. The vessel was connected to shaker-type hydrogenation
to it. The vessel was connected to a shaker-type hydrogenation apparatus and hydrogen atmosphere of 60 psi was maintained
apparatus and a hydrogen atmosphere of 60 psi was maintained inside the reaction vessel at room temperature for 8 h. The
inside the reaction vessel at room temperature for 9 h. The reaction mixture was then filtered through celite pad. The
reaction mixture was then filtered by vacuum through celite solvent was evaporated under vacuum and the resulted product
pad. Solvent was evaporated under vacuum. The resulted was purified by column chromatography using basic silica gel as
product was purified by column chromatography using silica gel the stationary phase and 20% ethyl acetate–hexane as the
as the stationary phase and 40% ethyl acetate–hexane as the mobile phase, producing 9 as colorless crystals (3.77 g,
mobile phase produced 6 as pale yellow crystals (0.14 g, 27.9 mmol). Yield: 92%. M.p.: 108–1101C [lit.100–1011C].38 1H
0.59 mmol). Yield: 86%. M.p.: 227–2281C. 1H NMR (300 MHz, NMR (300 MHz, CDCl3, d): 7.30 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.21
DMSO-d6, d): 8.83 (d, J = 4.5 Hz, 1H), 8.82 (s, 1H), 7.42 (d, (t, J = 7.7 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.80 (s, 2H), 2.50 (s, 3H).
13
J = 4.6 Hz, 1 H), 7.25 (s, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 7.12 C NMR (75.5 MHz, CDCl3, d): 198.4, 146.8, 138.2, 129.4, 119.6,
(d, J = 7.7 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.43 (s, 2H). 13C NMR 118.7, 114.0, 26.6. IR (KBr, thin film): 3467, 3370, 1668, 1627,
(75.5 MHz, DMSO-d6, d): 154.0, 151.6, 149.2, 149.0, 147.6, 130.4, 1599, 1491, 1458, 1321, 870, 778, 685 cm
1. MS-EI (m/z): 135
129.6, 117.5, 117.451, 114.8, 113.9, 110.7, 81.6. IR (KBr, thin film): (M1, 94), 120 (93), 92 (100), 66 (25), 65 (89), 63 (27). HRMS-EI (m/
2916, 2221, 1447, 846, 783 cm
1. MS-EI (m/z): 235 (M1, 100), 234 z): [M]1 calcd. for C8H9NO, 135.0684; found 135.0689.
74

www.jlcr.org Copyright r 2008 John Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2008, 51 72–76
A. C. Shaikh and C. Chen

Synthesis of N-(3-acetyl-phenyl)-acetamide (10): Acetic anhy- collected by filtration, washed with water and dried in vacuo to
dride (9.58 mL, 101.4 mmol) and pyridine (9.58 mL, 118.5 mmol) afford 8 as colourless crystals (2.2 g, 7.0 mmol). Yield: 84%. All
were successively added to the 1-(3-amino-phenyl)-ethanone (9) spectral data are identical to the previously synthesized
(2.74 g, 20.3 mmol). This reaction mixture was stirred at room compound 8.
temperature for 1 h under argon. The mixture was then slowly
poured into stirring water; the temperature was increased Acknowledgements
suddenly. This aqueous layer was extracted by ethyl acetate and
collected organic layer was dried over anhydrous Na2SO4 and The authors thank Ms Hsu, L. M. at the Instruments Center,
concentrated to give 10 as white solid (3.56 g, 20.1 mmol). Yield: National Chung Hsing University, for her help in obtaining
99%. M.p.: 140–1411C. 1H NMR (300 MHz, CDCl3, d): 8.66 (br s, HRMS. The authors would also like to thank the National Bureau
1H), 8.05 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.62 (d, of Controlled Drugs, Department of Health, Taiwan, Republic of
J = 9.0 Hz, 1H), 7.36 (t, J = 9.0 Hz, 1H), 2.55 (s, 3H), 2.19 (s, 3H). 13C China, for financially supporting this work under Contract
NMR (75.5 MHz, CDCl3, d): 198.4, 169.3, 138.8, 137.5, 129.2, 124.7, DOH95-NNB-1001.
124.0, 119.3, 26.7, 24.4. IR (KBr, thin film): 3355, 2359, 1702, 1672,
1591, 1482, 1278, 1213, 905, 797, 695, 545 cm
1. MS-EI (m/z): 177
(M1, 89), 135 (91), 120 (100), 105 (35), 92 (52), 65 (24). HRMS-EI References
(m/z): [M]1 calcd. for C10H11NO2, 177.0790; found 177.0781.
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95%. M.p.: 184–1861C. 1H NMR (300 MHz, CD3OD, d): 8.00 (s, 1H), 1187–1200.
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36.2, 22.4. IR (KBr, thin film): 3264, 2356, 1687, 1637, 1414, 1317, 1143–1147.
1281, 1116, 791 cm
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(98), 189 (22), 147 (31), 98 (100), 70 (39), 55 (35). HRMS-EI (m/z): 109–110.
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anhydrous Na2SO4 and evaporated in vacuo to yield 12 (2.22 g, Stanski, Clin. Ther. 2000, 22, 1443–1461.
8.36 mmol). Yield: 84%. M.p.: 113.5–114.51C. 1H NMR (400 MHz, [18] D. R. Drover, Clin. Pharmacokinet. 2004, 43, 227–238.
CD3OD, d): 7.90 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 12.0 Hz, 1H), 7.71 (s, [19] S. I. Ganzberg, T. Dietrich, M. Valerin, F. M. Beck, Anesth. Prog. 2005,
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J = 12.0 Hz, 1H), 3.15 (s, 3H), 2.95 (s, 3H), 1.76 (s, 3H). 13C NMR dia.org/wiki/Zaleplon. Wikimedia Foundation Inc. Florida, USA.
(75.5 MHz, CD3OD, d): 187.5, 170.8, 155.9, 142.6, 142.1, 130.5, [21] J. Glass, K. L. Lanctot, N. Herrmann, B. A. Sproule, U. E. Busto, Brit.
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1424, 1286, 1190, 1172, 910, 762, 619 cm
1. MS-EI (m/z): 265 (M1 976–978.
, 44), 248 (36), 222 (17), 205 (25), 173 (13), 144 (13), 98 (100), 70 [24] M. G. Terzano, M. Rossi, V. Palomba, A. Smerieri, L. Parrino, Drug
(12). HRMS-EI (m/z): [M]1 calcd. for C15H15D5N2O2, 265.1834; Saf. 2003, 26, 261–282.
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