Synthesis of deuterium-labeled zaleplon-d5 as an internal standard

Article abstract of DOI:10.1002/jlcr.1484

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. Copyright

Full text of DOI:10.1002/jlcr.1484

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
Ã
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
are required to ensure accurate analyses of controlled substance
and related compounds. To our knowledge synthesis of stable-
Introduction
Drugs of abuse are typically detected and identified by gas
chromatography-mass spectrometry (GC-MS) because of the
high sensitivity of this method and its ability to separate
complex mixtures of organic compounds.1–4 Standard samples
used for analyzing controlled drugs in Taiwan are very difficult
to obtain. The use of deuterium-labeled controlled drugs as
internal standards for use in GC-MS analysis is well documen-
ted.5–9 This work describes a synthesis of zaleplon-d5, which can
serve as an internal standard for the identification of zaleplon by
GC-MS analysis.
Zaleplon is a pyrazolopyrimidine sedative–hypnotic10,11 agent
for the treatment of insomnia.11 Other members of this class
include zopiclone, zolpidem and eszopiclone.12 Zaleplon is a
short acting benzodiazepine-like hypnotic drug, which is
licensed for the short-term treatment of patients with insomnia
who experience early morning awakening. It does not increase
sleep duration, unlike other hypnotics.13
Investigations into the action of zaleplon have demonstrated
that it selectively binds to the benzodiazepine type 1 site on the
c-aminobutyric acid subtype A (GABAA) receptor/chloride-ion
channel complex.14,15 It has a short action onset time, peak
plasma concentration time and elimination half-life of approxi-
mately 1 h each.16 Zaleplon is effective in treating insomnia with
fewer residual central nervous system or ‘hangover’ effects than
are observed in patients on other drugs of the benzodiazepine
group.17–19 These advantages have resulted in an enormous
increase in the use of zaleplon worldwide.
Zaleplon is reportedly a habit-forming drug, meaning that
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.
labeled standard for analyzing zaleplon has not been published.
Accordingly, an approach for synthesizing such a standard is
described herein.
Results and discussion
Our first route to zaleplon-d5 is shown in Scheme 1. Initially, 30-
nitroacetophenone 1 was treated with N,N-dimethylformamide
dimethylacetal under reflux to yield the intermediate, enamide
2.29,30 Another key intermediate, 5-amino-1H-pyrazole-4-carbo-
nitrile (4) was obtained by refluxing ethoxymethylenemalononi-
trile (3) and hydrazine hydrate in ethanol.31 In the following step,
compounds 4 and 2 underwent cyclization under mild acidic
condition at reflux to yield 7-(3-nitro-phenyl)-pyrazolo[1,5-a]-
pyrimidine-3-carbonitrile (5).29 An efficient reduction of 5 using
10% Pd/C catalyst at an H2 pressure of 60 psi gave
7-(3-amino-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (6).
The 3-amino phenyl pyrazolopyrimidine 6 was treated with an
acetic anhydride and pyridine to produce acetamide 7.32
Introduction of the isotopic label was attempted by treating
acetamide 7 with ethyl iodide-d5
in the presence of sodium
hydride, under an inert atmosphere at 501C. Unfortunately, the
yield of zaleplon-d5 so obtained was insignificant. Various
alternative conditions were tried but the maximum yield
obtained was only 20%.33 The purification of zaleplon-d5 was
also problematical as zaleplon-d5 could not be successfully
crystallized and elution from a silica column was difficult.
Therefore, this route was abandoned.
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974,
Taiwan, Republic of China
Zaleplon is regulated as a controlled drug in some countries
such as the United States,26 because an increasing number of
investigations have reported abuse and intoxication.10,27,28
High-purity standards, including isotopically labeled analogs,
*Correspondence to: Chinpiao Chen, Department of Chemistry, National Dong
Hwa University, Soufeng, Hualien 974, Taiwan, Republic of China.
E-mail: chinpiao@mail.ndhu.edu.tw
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
reflux, 19 h, 87%
NMe2
NO2
NO2
NO2
AcOH, reflux
12 h, 87%
1
2
N
N
NC
EtO
CN
CN
N2H4.H2O, EtOH
reflux, 3.5 h, 57%
N
N
CN
H
N
H
5
H2N
3
4
C2D5
NAc
NHAc
NH2
EtI-d5, NaH, THF
50°C, 60 h, 20%
Ac2O, pyridine
rt, 20 h, 88%
10% Pd/C, H2 (60 psi)
EtOAc, rt, 9 h, 82%
N
N
N
N
N
N
N
N
N
CN
CN
CN
8
7
6
Scheme 1
O
O
O
Me
(MeO)2CHN(Me)2
reflux, 14 h, 95%
Me
Me
Ac2O, Pyridine
rt, 1 h, 99%
10% Pd/C, H2 (60 psi)
EtOAc, rt, 8 h, 92%
NO2
NH2
NHAc
1
9
10
NC
C2D5
N
N
N
Me
C2D5
NAc
NHAc
H2N
H
4
O
EtI-d5, NaH, DMF
0°C to rt, 1 h, 96%
aq. AcOH, 50°C
2 h, 85%
N
N
O
NMe2
O
NMe2
N
CN
11
8
12
Scheme 2
Dusza et al. described another route that satisfied our yield
requirements, shown in Scheme 2.34 Their synthesis started from
compound 10, which is not commercially available. Therefore,
the route was modified to start with compound 1, which is
readily available and inexpensive. 30-Nitroacetophenone 1 was
reduced to 30-aminoacetophenone 935 and subsequent acyla-
tion yielded the acetamide 10, which in turn was treated with
N,N-dimethylformamide dimethylacetal to produce enamide 11.
Enamide 11 was alkylated using ethyl iodide-d5 and sodium
hydride as base at room temperature to yield the N-ethylated
enamide 12.34 In the final step, N-ethylenamide 12 was coupled
with 5-aminopyrazole 4 in aqueous acid at 501C to produce
zaleplon-d5 8 in 85% yield.36 Further purification by recrystalliza-
tion of the crude product from 30% aqueous acetic acid yielded
colorless crystals of zaleplon-d5 8.37
Experimental
General
1H NMR spectra were acquired at 300 and 400 MHz (indicated in
each case), and 13C NMR were acquired at 75.5 MHz on a Bruker
NMR spectrometer. Chemical 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 spectrometer.
All reactions were performed in anhydrous solvents. Tetrahy-
drofuran and diethyl ether were distilled from sodium-benzo-
phenone in argon. Benzene and N,N-dimethylformamide were
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.
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.
Synthesis of 3-dimethylamino-1-(3-nitro-phenyl)-2-propen-1-one
C13H9N5, 235.0858; found 235.0862.
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 cmꢀ1
.
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 cmꢀ1. 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,
1
crystals (2.62 g, 9.9 mmol). Yield: 70%. M.p.: 213–2141C. H 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):
13C 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 cmꢀ1
.
728 cmꢀ1. 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.
Synthesis of 7-(3-amino-phenyl)-pyrazolo[1,5-a]pyrimidine-3-
310.1585; found 310.1588.
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).
J = 4.6 Hz, 1 H), 7.25 (s, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 7.12 13C 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 cmꢀ1. 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 cmꢀ1. MS-EI (m/z): 235 (M1, 100), 234 z): [M]1 calcd. for C8H9NO, 135.0684; found 135.0689.
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,
National Chung Hsing University, for her help in obtaining
HRMS. The authors would also like to thank the National Bureau
of Controlled Drugs, Department of Health, Taiwan, Republic of
China, for financially supporting this work under Contract
DOH95-NNB-1001.
concentrated to give 10 as white solid (3.56 g, 20.1 mmol). Yield:
1
99%. M.p.: 140–1411C. H NMR (300 MHz, CDCl3, d): 8.66 (br s,
1H), 8.05 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.62 (d,
J = 9.0 Hz, 1H), 7.36 (t, J = 9.0 Hz, 1H), 2.55 (s, 3H), 2.19 (s, 3H). 13
C
NMR (75.5 MHz, CDCl3, d): 198.4, 169.3, 138.8, 137.5, 129.2, 124.7,
124.0, 119.3, 26.7, 24.4. IR (KBr, thin film): 3355, 2359, 1702, 1672,
1591, 1482, 1278, 1213, 905, 797, 695, 545 cmꢀ1. MS-EI (m/z): 177
(M1, 89), 135 (91), 120 (100), 105 (35), 92 (52), 65 (24). HRMS-EI
(m/z): [M]1 calcd. for C10H11NO2, 177.0790; found 177.0781.
Synthesis of N-[3-(3-dimethylamino-acryloyl)-phenyl]-acetamide
(11): A mixture of N-(3-acetyl-phenyl)-acetamide (10) (2.26 g,
12.8 mmol) and N,N-dimethylformamide dimethylacetal (6.1 mL,
45.9 mmol) was refluxed for 14 h. The reaction mixture was
cooled to room temperature and the excess solvent was
evaporated in vacuo to afford 11 (2.79 g, 12.0 mmol). Yield:
95%. M.p.: 184–1861C. 1H NMR (300 MHz, CD3OD, d): 8.00 (s, 1H),
7.80 (d, J = 12.0 Hz, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 7.8 Hz,
1H), 7.35 (t, J = 7.9 Hz, 1H), 5.75 (d, J = 12.2 Hz, 1H), 3.17 (s, 3H),
2.97 (s, 3H), 2.12 (s, 3H). 13C NMR (75.5 MHz, CD3OD, d): 189.3,
170.3, 155.7, 140.9, 138.6, 128.3, 122.7, 122.3, 118.7, 91.8, 44.1,
36.2, 22.4. IR (KBr, thin film): 3264, 2356, 1687, 1637, 1414, 1317,
1281, 1116, 791 cmꢀ1. MS-EI (m/z): 232 (M1, 94), 216 (25), 215
(98), 189 (22), 147 (31), 98 (100), 70 (39), 55 (35). HRMS-EI (m/z):
[M]1 calcd. for C13H16N2O2, 232.1212; found 232.1204.
References
[1] C. R. Clark, J. DeRuiter, A. Valaer, F. T. Noggle, J. Chromatogr. Sci.
1995, 33, 328–337.
[2] F. T. Noggle, C. R. Clark, K. H. Bondir, J. DeRuiter, J. Chromatogr. Sci.
1991, 29, 103–106.
[3] T. A. Dal Cason, Forensic Sci. Int. 1990, 35, 675–697.
[4] W. H. Soine, R. E. Shark, D. T. Agee, J. Forensic Sci. 1983, 28,
386–390.
[5] Y. Z. Xu, C. Chen, J. Label. Compd. Radiopharm. 2006, 49,
1187–1200.
[6] Y. Z. Xu, C. Chen, J. Label. Compd. Radiopharm. 2006, 49, 897–902.
[7] Y. Z. Xu, C. Chen, J. Chin. Chem. Soc. 2007, 54, 493–502.
[8] A. C. Shaikh, Y. Y. Wang, C. Chen, J. Label. Compd. Radiopharm.
2007, 50, 660–665.
[9] Y. J. Chen, C. Chen, J. Label. Compd. Radiopharm. 2007, 50,
1143–1147.
[10] S. C. Bhatia, M. Arora, S. K. Bhatia, Psychiatr. Serv. 2001, 52,
109–110.
[11] A. B. Renwick, H. Mistry, S. E. Ball, D. G. Walters, J. Kao, B. G. Lake,
Xenobiotica 1998, 28, 337–348.
Synthesis of N-[3-(3-dimethylamino-acryloyl)-phenyl]-N-ethyl-
acetamide-d5 (12): A mixture of N-[3-(3-dimethylamino-acry-
loyl)-phenyl]-acetamide (11) (2.28 g, 9.8 mmol) and sodium
hydride (0.45 g, 19.6 mmol) in dimethylformamide (20 mL) was
stirred for 30 min under argon, then cooled in an ice bath, and a
solution of ethyl iodide-d5 (0.98 ml, 12.3 mmol) in dimethylfor-
mamide (10 mL) was added in small portions. The mixture was
then stirred at room temperature for 30 min and extracted three
times with hexane. The extracts were discarded, water was
added and this aqueous solution was again extracted with
dichloromethane. The collected organic layer was dried over
anhydrous Na2SO4 and evaporated in vacuo to yield 12 (2.22 g,
[12] B. D. Brielmaier, Baylor University Medical Center Proceeding, 2006,
19, pp. 54–59. Department of Pharmacy Services, Baylor University
Medical Center, Dallas, Texas, USA.
[13] Report of Regional Drug and Therapeutics Centre, No. 41, June 2000,
http://www.ukmi.nhs.uk/NewMaterial/html/docs/26120016.pdf .
[14] D. J. Sanger, E. Morel, G. Perrault, Eur. J. Pharmacol. 1996, 313,
35–42.
[15] S. Ancoli-Israel, J. K. Walsh, R. M. Mangano, M. Fujimori, J. Clin.
Psychiatry 1999, 1, 114–120.
[16] B. Beer, J. R. Ieni, W. H. Wu, D. Clody, P. Amorusi, J. Rose, T. Mant,
J. Gaudreault, A. Cato, W. Stern, J. Clin. Pharmacol. 1994, 34,
335–344.
[17] D. Drover, H. Lemmens, S. Naidu, W. Cevallos, M. Darwish, D.
Stanski, Clin. Ther. 2000, 22, 1443–1461.
[18] D. R. Drover, Clin. Pharmacokinet. 2004, 43, 227–238.
[19] S. I. Ganzberg, T. Dietrich, M. Valerin, F. M. Beck, Anesth. Prog. 2005,
52, 128–131.
[20] Zaleplon-Wikipedia, the Free Encyclopedia, http://en.wikipe-
dia.org/wiki/Zaleplon. Wikimedia Foundation Inc. Florida, USA.
[21] J. Glass, K. L. Lanctot, N. Herrmann, B. A. Sproule, U. E. Busto, Brit.
Med. J. 2005, 331, 1169–1176.
[22] G. K. Zamit, J. A. Kramer, J. Clin. Psychiatry 2001, 3, 53–60.
[23] M. A. Scott, S. Stigleman, D. Cravens, J. Fam. Pract. 2003, 52,
976–978.
1
8.36 mmol). Yield: 84%. M.p.: 113.5–114.51C. H NMR (400 MHz,
CD3OD, d): 7.90 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 12.0 Hz, 1H), 7.71 (s,
1H), 7.54 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.82 (d,
J = 12.0 Hz, 1H), 3.15 (s, 3H), 2.95 (s, 3H), 1.76 (s, 3H). 13C NMR
(75.5 MHz, CD3OD, d): 187.5, 170.8, 155.9, 142.6, 142.1, 130.5,
129.5, 126.9, 126.7, 91.4, 44.3, 43.8 (m, very weak), 36.4, 21.5, 11.9
(m, very weak). IR (KBr, thin film): 3042, 2360, 1632, 1550, 1481,
1424, 1286, 1190, 1172, 910, 762, 619 cmꢀ1. MS-EI (m/z): 265 (M1
, 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.
[25] M. H. Beers, Arch. Intern. Med. 1997, 157, 1531–1536.
[26] Letter of Neil Yeates, Assistant Deputy Minister, Health Canada, to
found 265.1835.
Synthesis of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phe-
nyl]-N-[2H5]-ethyl-acetamide (8): (Scheme 2) A mixture of N-[3-
Provincial and Territorial Deputy Ministersof Health, Deans of
Pharmacy, Industry and Consumer Associations, Regulatory and
Health Professional Associations, 05-109409-263.
[27] WHO Expert Committee on Drug Dependence. Thirty-third report.
Geneva, World Health Organization, 2003 (WHO Technical Report
Series, No. 915).
[28] C. R. Rush, J. M. Frey, R. R. Griffiths, Psychopharmacology 1999, 145,
39–51.
(3-dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide-d5 (12)
(2.22 g, 8.4 mmol), 3-aminopyrazol-4-carbonitrile (4) (0.90 g,
8.37 mmol), acetic acid (6.2 mL) and water (19.2 mL) was heated
to 501C. After about 2 h, the reaction was stopped and the
mixture was cooled to 101C. The resulted crystalline product was
J. Label Compd. Radiopharm 2008, 51 72–76
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

A. C. Shaikh and C. Chen
[29] K. E. Andersen, A. S. Jørgensen, C. Bræstrup, Eur. J. Med. Chem.
1994, 29, 393–399.
[30] J. L. Collins, B. G. Shearer, J. A. Oplinger, S. Lee, E. P. Garvey, M.
elevated temperature were used. The best condition was found to
be THF, NaH and 501C.
[34] J. P. Dusza, A. S. Tomcufcik, J. D. Albright, US Patent 4,626,538.
Salter, C. Duffy, T. C. Burnette, E. S. Furfine, J. Med. Chem. 1998, 41, [35] B. Basu, S. Das, P. Das, A. K. Nanda, Tetrahedron Lett. 2005, 46,
2858–2871. 8591–8593.
[31] J. S. Larsen, M. A. Zahran, E. B. Pedersen, C. Nielsen, Monatsh. [36] T. Padmanathan, US Patent 5,714,607.
Chem. 1999, 130, 1167–1173. [37] E. Feher, F. Korodi, C. Singer, E. Magyar, US Patent WO 03/011228
´
´
[32] P. Rodrıguez-Loaiza, A. Quintero, R. Rodrıguez-Sotres, J. D. Solano,
A. Lira-Rocha, Eur. J. Med. Chem. 2004, 39, 5–10.
A2, PCT/US02/24553.
[38] A. I. Vogel, Text Book of Practical Chemistry, 5th ed. Revised by
Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR. Addison-
Wesely, Longman, UK, 1997, pp. 1298–1398.
[33] Various combinations of solvents, such as DMSO, DMF, and bases,
such as K2CO3 and KOH, and temperature conditions r.t. and
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 72–76