Synthesis of some impurities and/or degradation products of zaleplon

Article abstract of DOI:10.1002/jhet.335

(Chemical Equation Presented) Synthesis of several potential impurities and/or degradation products of zaleplon is identified. All the prepared compounds were unambiguously identified by NMR techniques. Spectral characteristics (IR, UV, MS) of these compo

Full text of DOI:10.1002/jhet.335

276
Synthesis of Some Impurities and/or Degradation Products
of Zaleplon
Vol 47
a
Stanislav Radl, * Michaela Blahovcova, Lukas Placek, Tomas Pekarek,
b
a
a
´
´
´ˇ
and Jaroslav Havlıcek
´ˇ
ˇ
´ˇ
´
a
aZentiva, U kabelovny 130, 102 01 Prague 10, Czech Republic
b
´
´ ´
Pharmaceuticl Faculty of the Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove,
Czech Republic
*E-mail: stanislav.radl@zentiva.cz
Received August 19, 2009
DOI 10.1002/jhet.335
Published online 20 January 2010 in Wiley InterScience (www.interscience.wiley.com).
Synthesis of several potential impurities and/or degradation products of zaleplon is identified. All the
prepared compounds were unambiguously identified by NMR techniques. Spectral characteristics (IR,
UV, MS) of these compounds are also given.
J. Heterocyclic Chem., 47, 276 (2010).
INTRODUCTION
with 5-amino-1H-pyrazol-4-carbonitrile (3a) under
acidic conditions. The original patent [4] describes the
reaction in anhydrous acetic acid, but under these condi-
tions considerable amounts of the corresponding isomer
4 is formed. Much better results are achieved using
aqueous acetic [5] or formic [6] acids. Probably the best
results regarding purity and yields are obtained when
the reaction is done in aqueous alcohols in the presence
of hydrochloric acid [7,8] (Scheme 1).
Zaleplon (1) is a nonbenzodiazepine hypnotic belong-
ing with zolpidem and zopiclon to the so-called Z-hyp-
notic class [1,2]. Clinical results have shown that zale-
plon is efficacious in the treatment of insomnia where
difficulty in falling asleep is the primary problem. Zale-
plon unlike many other hypnotic drugs does not inter-
fere with sleep architecture and can be administered for
up to 5 weeks without the risk of dependence or
rebound insomnia upon discontinuation [3].
One of the principal parts of documentation of any
active pharmaceutical ingredient (API) is description of
impurities and/or degradation products which can be
present. Identified impurities should be included in the
specification when they are present at a level higher
than the identification threshold, which is usually
0.10%. These impurities must be not only identified but
also either isolated or independently synthesized.
Several impurities of zaleplon, including regioisomer
4 and compounds 5–8, have recently been isolated and
identified [9]. We have recently reported synthesis of
zaleplon regioisomer 4 based on the Suzuki-Miyaura
coupling [10]. To the best of our knowledge, no report
on the synthesis of compounds 5–8 has been published
Most of the described methods [4–7] of preparation
of zaleplon are based on reaction of N-[3-[(2E)-3-(dime-
thylamino)prop-2-enoyl]phenyl]-N-ethylacetamide (2a)
C
V
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Synthesis of Some Impurities and/or Degradation Products of Zaleplon
277
Scheme 1. Formation of zaleplon (1) and its regioisomer 4.
and therefore we decided to synthesize these and other
potential impurities as standards.
of the corresponding impurities in 2 with 3a. On the
other hand, compounds 7 and 8 are products of hydroly-
sis of zaleplon leading to the nitrile group hydrolysis
and anilide group hydrolysis, respectively. Our initial
stress tests of zaleplon envisaged also formation of other
similar impurities, as shown in Scheme 2, and therefore
we decided to synthesise them.
RESULTS AND DISCUSSION
During our development of generic zaleplon, we
decided to prepare compounds 5–13 as standards. Com-
pounds 5 and 6 were prepared analogously as zaleplon
starting from commercially available compound 2b and
compound 2c, respectively. Compound 2c was prepared
From the structures, it is evident that compounds 5
and 6 are process-related impurities formed by reaction
Scheme 2. Possible degradation pathways of zaleplon under stress tests conditions.
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S. Radl, M. Blahovcova, L. Placek, T. Pekarek, and J. Havlıcek
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Scheme 3. Preparation of process-related impurities 5 and 6 and impurity 8.
from 2b using sodium hydride/iodomethane. For the
synthesis of compounds 8, 11–13, we decided to start
from 2d (R1 ¼ CHO, R2 ¼ H), which was easily
obtained from 3-aminoacetophenone by subsequent for-
mylation, folowed by treatment with DMFDMA. Com-
pound 2d then provided 2e using NaH/DMF and EtI.
1H NMR spectra of all of the compounds 2 showed
that the methyl groups are nonequivalent as a result of
the hindered rotation of dimethylamino group.
corresponding formyl derivative 14 was obtained
(Scheme 3).
We intended to prepare amide impurity 7 by aminoly-
sis of the corresponding ethyl ester and we also hoped
that hydrolysis of this ester can provide acid 9. For this
purpose we prepared pyrazolecarboxylate 3b using a
modification of the literature procedure [11]. Similarly,
also the corresponding benzyl ester 3c was prepared
[12]. Using general procedure described above, starting
from compounds 2a and 2e, esters 15-18 were prepared
(Scheme 4).
Compounds 2b and 2c heated with pyrazole 3a in
EtOH or MeOH and small amounts of concentrated hy-
drochloric acid provided good yields of the correspond-
ing products 5 and 6. Formyl derivative 2e under the
same conditions, was completely deprotected to give
compound 8. When the reaction was done with anhy-
drous solution of HCl in EtOH or in formic acid, the
Aminolysis of both esters 15 and 16 to the corre-
sponding amides 19 and 20 was very sluggish even
using saturated ethanolic ammonia at 100ꢀC under pres-
sure; the mixtures after five days still contain about 10%
of the starting compounds. Compound 19 was also
Scheme 4. Preparation of esters 15–18.
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Synthesis of Some Impurities and/or Degradation Products of Zaleplon
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Scheme 5. Aminolysis of esters 15 and 16.
obtained using catalysis [13] with MgBr2, which short-
ened the reaction time but the crude mixture contained
several impurities not present in case the reaction was
done without the catalyst (Scheme 5).
However, we found that at 50ꢀC in acetic acid the reac-
tion is clean to give the required product 9 in good
yield. Similarly, using formic acid and the following hy-
drolysis with aqueous hydrochloric acid, unsubstituted
compound 12 was obtained (Scheme 7).
Our initial attempts to synthesize acid 9 by hydrolysis
of the corresponding ester 15 led under all conditions
used to complex mixtures. Therefore the benzyl esters
17 and 18 were prepared and their hydrogenolytic
debenzylation provided the corresponding acids 9 and
12 (Scheme 6). However, prolongation of the reaction
time led to partial overreduction providing compounds
having molecular weight higher by 4H (LC-MS).
EXPERIMENTAL
Reagents used in the synthesis were purchased from Sigma-
Aldrich and were used without purification.
Melting points were measured on a Kofler block and are
uncorrected. The IR spectra were measured on a Nicolet
Nexus FTIR instrument (Thermo) by accumulation of 64 scans
with 4 cmꢁ1 resolution using the ATR technique (ZnSe crys-
tal); wavenumbers are given in cmꢁ1. The UV spectra were
Initially we tried to avoid direct condensation of com-
pounds 2a and 2e with 3-amino-4-pyrazol carboxylic
acid (3d) and its amide (3e) since we expected partial
hydrolysis and decarboxylation during the reaction.
When we tried to do the reaction of 2a with 3d in a
mixture of ethanol and hydrochloric acid, a mixture of
the required acid 9 and its ethyl ester 15 was formed.
recorded on
a Hewlett-Packard 8452A spectrophotometer
(ethanol) in the range 190–400 nm. NMR experiments were
carried out on a Bruker Avance 250. The Mass spectra [MS/
MS; ionization mode APCI(þ)] were measured on an API
3000 PE machine (Sciex Instruments, Applied Biosystems).
Scheme 6. Debenzylation of benzyl esters 17 and 18.
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Scheme 7. Preparation of amides and acids by direct condensation.
The purity of the prepared substances was evaluated by TLC
on silica gel (FP KG F 254, Merck). Flash chromatography
was performed on silica gel Merck, particle size 0.04–0.063
mm. Centrifugally accelerated axial chromatography was done
using CyclographTM instrument (Analtech) with silica gel pre-
scraped rotors.
N-[3-[(2E)-3-(Dimethylamino)prop-2-enoyl]phenyl]-N-me-
thylacetamide (2c). N-[3-[(2E)-(3-(Dimethylamino)prop-2-
enoyl]phenyl]acetamide (2b, 5.8 g, 25 mmol) was added to a
stirred 50% suspension of NaH (1.5 g) in DMF (80 mL) and
the mixture was stirred under nitrogen for 1 h. Then a solu-
tion of iodomethane (5 g, 35 mmol) in DMF (10 mL) was
added dropwise to the mixture and stirred at ambient temper-
ature for 2.5 hrs. The mixture was poured into water (300
mL), washed with hexane and then the aqueous layer was
extracted with CH2Cl2 (5 ꢂ 50 mL, 5 ꢂ 20 mL). The extract
was washed with brine and dried with MgSO4. Crystallization
of the residue after evaporation from ethyl acetate provided
5.2 g of yellow crystals (91%), mp 140–144ꢀC. IR: CH 2815,
N-[3-[(2E)-3-(Dimethylamino)prop-2-enoyl]phenyl]forma-
mide (2d). A solution of N-(3-acetylphenyl)formamide (3.25
g, 20 mmol) and DMFDMA (4.5 g, 37.8 mmol) in DMF (8
mL) was refluxed for 8 hrs and then stirred overnight. The
formed yellow crystals were filtered off; yield 2.5 g (66%), mp
162–165ꢀC. IR: NH 3229, 3184, CH 3066, 2846, 2767, C¼¼O
1698, 1636, C¼¼C 1595, 1516 cmꢁ1
.
1H NMR (DMSOd6): d
2.91 (s, 3H, NCH3), 3.14 (s, 3H, NCH3), 5.73 (d, 1H, J ¼
12.5, [dnond]CHCO), 7.37-8.01 (m, 5H, ArAH, ¼¼CHAN),
8,30 (s, 1H, CHO), 10.23 (bs, 1H, NH). Anal. Calcd. for
C12H14N2O2: C 66.04; H 6.47; N 12.84. Found: C 66.21; H
6.67; N 13.01. HRMS Calcd. for C12H15N2O2 (MþH)þ
219.11335. Found: 219.11310.
N-[3-[(2E)-3-(Dimethylamino)prop-2-enoyl]phenyl]-N-eth-
ylformamide (2e). Compound 2d (2.52 g, 11.6 mmol) was
added to a stirred 50% suspension of NaH (0.7 g, 14.6 mmol)
in DMF (40 mL), and the mixture was stirred under nitrogen
for 1 h. The mixture was cooled with ice-water and a solution
of iodoethane (2.3 g, 15 mmol) in DMF (5 mL) was added
dropwise and stirred at ambient temperature for 4 hrs. After
that the mixture was poured into water and extracted with
CH2Cl2. The extract was washed with brine and dried with
MgSO4. Crystallization of the residue after evaporation from
ethyl acetate provided 0.63 g of yellow crystals (22%), mp
69–73ꢀC. IR: CH 2922, 2809, C¼¼O 1667, 1634, C¼¼C 1548,
C¼¼O 1637, C¼¼C 1585, 1538, CH 1367 cmꢁ1
.
1H NMR
(CDCl3): d 1.89 (s, 3H, CH3CO), 2.88 (s, 3H, NCH3), 3.17
(s, 3H, NCH3), 3.29 (s, 3H, NCH3), 5.65 (d, J ¼ 12.5, 1H,
¼¼CHCO), 7.26-7.87 (m, 5H, ArAH, ¼¼CHAN); 13C NMR
(CDCl3): 22.45, 37.10, 45.15, 91.66, 126.07, 126.62, 129.29,
129.43, 142.32, 144.56, 154.65, 170.46, 186.96. Anal. Calcd.
for C14H18N2O2: C 68.27; H 7.37; N 11.37. Found: C 68.22;
H 6.94; N 11.06. HRMS Calcd. for C14H19N2O2 (MþH)þ
247.14465. Found: 247.14406.
1
1482 cmꢁ1. H NMR (CDCl3): d 1.17 (t, 3H, J ¼ 7.2, CH3),
2.96 (s, 3H, NCH3), 3.17 (s, 3H, NCH3), 3.85 (q, 2H, J ¼ 7.2,
NCH2), 5.71 (d, 1H, J ¼ 12.3, ¼¼CHCO), 7.23-7.86 (m, 5H,
ArAH, ¼¼CHAN), 8.38 (s, 1H, CHO). Anal. Calcd. for
C14H18N2O2: C 68.27; H 7.37; N 11.37. Found: C 68.21; H
7.52; N 11.51. HRMS Calcd. for C14H19N2O2 (MþH)þ
247.14465. Found: 247.14392.
N-(3-Acetylphenyl)formamide. A mixture of 3-aminoaceto-
phenone (10 g, 0.07 mol) and formic acid (100 mL) was
refluxed for 10 hrs. Residue after evaporation was then crystal-
lized from toluene (charcoal) to provide 10.5 g of beige crys-
tals (87%); mp 92–94ꢀC [ref. 14 mp 93–94ꢀC (Et2O)]. IR: NH
3256, 3194, 3139, CH 3076, 3021, C¼¼O 1667, C¼¼C 1591,
General procedure for the synthesis of compounds 5, 6,
15, 17. Typically, a mixture of 3-(dimethylamino)-1-phenyl-
prop-2-en-1-one 2 (10 mmol) and pyrazole 3 (10 mmol), etha-
nol (50 mL) and hydrochloric acid (1 mL) was refluxed for 1
h. The mixture was cooled down, the formed precipitate was
filtered off to give the crude product, which was then crystal-
lized from an appropriate solvent.
1556, 1477 cmꢁ1 1H NMR (CDCl3): d 2.61 (s, 3H, CH3),
.
7.27-8.07 (m, 4H, ArAH), 8.44 (s, 1H, CHO). Anal. Calcd. for
C9H9NO2: C 66.25; H 5.56; N 12.06. Found: C 66.38; H 5.78;
N 12.34. HRMS Calcd. for C9H10NO2 (MþH)þ 164.07116.
Found: 164.07104.
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N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide
(5). This compound was obtained after crystallization from i-
PrOH in 77% yield according to the above general procedure;
mp 257–261ꢀC (ref. 15 mp 254–255ꢀC). IR: NH 3314, CH
3092, CN 2235, C¼¼O 1687, C¼¼C þ C¼¼N 1615, 1583, 1538,
1478 cmꢁ1. UV kmax (log e): 204 (4.30), 234 (4.60), 338
(3.91). 1H NMR (CDCl3): d 2.09 (s, 3H, CH3CO), 7.50-8.34
(m, 5H, ArAH), 8.86 (s, 1H, H-2), 8.90 (d, 1H, J ¼ 5.0, H-5),
10.23 (bs, 1H, NH). 13C NMR (CDCl3): 23.94, 81.34, 110.62,
113.37, 119.89, 122.01, 124.27, 129.05, 129.82, 139.41,
147.20, 147.51, 151.05, 153.71, 168.65. Anal. Calcd. for
C15H11N5O: C 64.97; H 4.00; N 25.26. Found: C 65.22; H
N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-eth-
ylformamide (14). A mixture of 2e (0.62 g, 2.5 mmol) and pyr-
azole 3a (0.3 g, 2.7 mmol) was dissolved in ethanol (10 mL)
and then a saturated solution of HCl in ethanol (1 mL) was
added. The mixture was refluxed for 3–4 hrs, evaporated and the
residue was crystallized from MeOH provided 0.45 g (62%) of
yellow crystals; mp 125–128ꢀC. IR: CH 3089, 2974, CBN
2230, C¼¼O 1678, C¼¼C þ C¼¼N 1611, 1552, 1493 cmꢁ1. UV
kmax (log e): 204 (4.41), 234 (4.63), 338 (3.89). 1H NMR
(CDCl3): d 1.24 (t, 3H, J ¼ 7.5, CH3), 3.95 (q, 2H, J ¼ 7.5
CH2), 7.14-8.65 (m, 8H, ArAH, NCHO). 13C NMR (CDCl3):
13.09, 40.15, 83.51, 109.90, 111.09, 112.48, 124.83, 126.98,
127.46, 130.36, 131.01, 141.54, 146.60, 147.17, 151.07, 152.60,
161.69. Anal. Calcd. for C16H13N5O: C 65.97; H 4.50; N 24.04.
Found: C 66.23; H 4.72; N 24.24. HRMS Calcd. for C16H14N5O
(MþH)þ 292.11984. Found: 292.11935.
3.94;
278.10419. Found: 278.10364.
N
12.26. HRMS Calcd. for C15H12N5O (MþH)þ
N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-meth-
ylacetamide (6). This compound was obtained after crystalliza-
tion from i-PrOH in 60% yield according to the above general
procedure; mp 202–205ꢀC. IR: CH 3075, CBN 2231, C¼¼O
1645, C¼¼C þ C¼¼N 1613, 1549, 1479 cmꢁ1. UV kmax (log e):
204 (4.40), 232 (4.58), 338 (3.85). 1H NMR (CDCl3): d 2.01
(s, 3H, CH3CO), 3.36 (s, 3H, CH3N), 7.21-7.51 (m, 2H,
ArAH), 7.68 (t, 1H, J ¼ 10.0, H-14), 7.94-7.99 (m, 2H,
ArAH), 8.44 (s, 1H, H-2), 8.81 (d, 1H, J ¼ 5.0, H-5). 13C
NMR (CDCl3): 22.63, 35.76, 83.73, 109.87, 112.51, 128.41,
129.57, 130.35, 131.03, 131.65, 143.47, 146.94, 147.11,
151.32, 152.61, 169.63. Anal. Calcd. for C16H13N5O: C 65.97;
H 4.50; N 24.04. Found: C 66.12; H 4.65; N 24.36. HRMS
Calcd. for C16H14N5O (MþH)þ 292.11983. Found: 292.11948.
Ethyl 7-[3-[acetyl(ethyl)amino]phenyl]pyrazolo[1,5-a]pyri-
midin-3-carboxylate (15). This compound was obtained after
crystallization from EtOH in 93% yield according to the above
general procedure; mp 127–132ꢀC. IR: OH 3390, CH 2971,
C¼¼O 1688, 1651, C¼¼C þ C¼¼N 1602, 1547, 1489 cmꢁ1. UV
kmax (log e): 206 (4.36), 234 (4.42), 340 (3.79). 1H NMR
(CDCl3): d 1.18 (t, 3H, J ¼ 7.1, NCH2CH3), 1.41 (t, 3H, J ¼
7.1, OCH2CH3), 1.95 (s, 3H, CH3CO), 3.81 (q, 2H, J ¼ 7.1,
NCH2), 4.45 (q, 2H, J ¼ 7.1, OCH2), 7.14 (d, 1H, J ¼ 2.7, H-
6), 7.29-8.01 (m, 4H, ArAH), 8.61 (s, 1H, H-2), 8.89 (d, 1H, J
¼ 2.7, H-5). 13C NMR (CDCl3): 13.11, 14.51, 23.00, 44.09,
60.47, 103.33, 109.11, 128.72, 129.60, 130.20, 131.11, 131.67,
143.30, 146.48, 147.41, 148.91, 152.44, 162.47, 169.87. Anal.
Calcd. for C19H20N4O3: C 64.76; H 5.72; N 15.90. Found: C
64.36; H 5.93; N 16.17. HRMS Calcd. for C19H21N4O3
(MþH)þ 353.16137. Found: 353.16077.
General procedure for the synthesis of compounds 8, 16,
18, 10, 13. Typically, a mixture of 3-(dimethylamino)-1-phenyl-
prop-2-en-1-one 2 (10 mmol), pyrazole 3 (10 mmol), ethanol
(50 mL) and 10% hydrochloric acid (10 mL) was refluxed for 1
h. The mixture was evaporated, the residue was triturated with
10% Na2CO3, the insoluble portion was filtered off to give the
crude product, which was then crystallized from an appropriate
solvent.
7-[3-(Ethylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-carboni-
trile (8). This compound was obtained after crystallization
from EtOH in 95% yield according to the above general proce-
dure; mp 172–179ꢀC. IR: CH 3071, 2707, 2662, 2478, CBN
2227, C¼¼C þ CAN 1612, 1544, 1495 cmꢁ1. UV kmax (log e):
1
206 (4.15), 234 (4.32), 338 (3.68). H NMR (DMSO): d 1.24
(t, 3H, J ¼ 7.5, CH3), 3.26 (q, 2H, J ¼ 7.5, CH2), 7.26-8.91
(m, 7H, ArAH). 13C NMR (DMSO): 12.75, 81.32, 110.65,
113.37, 129.60, 130.39, 147.20, 147.50, 151.05, 153.69. Anal.
Calcd. for C15H13N5: C 68.42; H 4.98; N 26.60. Found: C
68.18; H 4.73; N 26.86. HRMS Calcd. for C15H14N5 (MþH)þ
264.12492. Found: 264.12436.
Ethyl 7-[3-(ethylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-
carboxylate (16). This compound was obtained after crystalli-
zation from EtOH in 84% yield according to the above general
procedure; mp 189–202ꢀC. IR: CH 3072, 2664, 2485, C¼¼O
1705, C¼¼C þ C¼¼N 1611, 1581, 1548, 1494 cmꢁ1. UV kmax
1
(log e): 208 (4.31), 244 (4.44), 340 (3.84). H NMR (DMSO):
d 1.25 (t, 3H, J ¼ 7.2, NCH2CH3), 1.33 (t, 3H, J ¼ 7.2,
OCH2CH3), 3.29 (q, 2H, J ¼ 7.5, NCH2), 4.34 (q, 2H J ¼
7.2, OCH2), 7.33-7.90 (m, 5H, ArAH), 8.66 (s, 1H, H-2), 8.89
(d, 1H, J ¼ 5.0, H-5). 13C NMR (DMSO): 12.53, 14.40,
44.09, 59.55, 101.97, 109.88, 128.55, 129.61, 130.22, 130.98,
131.09, 131.76, 143.33, 146.68, 146.85, 148.16, 153.01,
161.69. Anal. Calcd. for C17H18N4O2: C 65.79; H 5.85; N
18.05. Found: C 65.47; H 6.04; N 18.25. HRMS Calcd. for
C17H19N4O2 (MþH)þ 311.15080. Found: 311.15021.
Benzyl 7-(3-(N-ethylacetamido)phenyl)pyrazolo[1,5-a]pyri-
midin-3-carboxylate (17). This compound was obtained after
flash chromatography (hexane–acetone 6 : 4) and following
crystallization from EtOH in 62% yield according to the above
general procedure (reaction time 4 hrs); mp 112–114ꢀC. IR:
CH 2968, 2930, C¼¼O 1694, 1652, C¼¼C þ C¼¼N 1610, 1545,
1
1480. UV kmax (log e): 206 (4.54), 234 (4.52), 340 (3.95). H
NMR (CDCl3): d 1.17 (t, 3H, J ¼ 7.2, CH3), 1.94 (s, 3H,
CH3CO), 3.82 (q, 2H, J ¼ 7.2, NCH2), 5.46 (s, 2H, OCH2),
7.12-8.00 (m, 10H, ArAH), 8.62 (s, 1H, H-2), 8.82 (d, 1H, J
¼ 5.0, H-5). 13C NMR (CDCl3): 13.12, 22.99, 44.07, 65.94,
103.08, 109.12, 128.05, 128.18, 128.50, 128.67, 129.61,
130.19, 131.12, 131.66, 136.42, 143.38, 146.47, 147.47,
149.15, 152.37, 162.10, 169.75. Anal. Calcd. for C24H22N4O3:
C 69.55; H 5.35; N 13.52. Found: C 69.44; H 5.39; N 11.67.
HRMS Calcd. for C24H23N4O3 (MþH)þ 415.17702. Found:
415.17682.
Benzyl 7-[3-(ethylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-
carboxylate (18). This compound was obtained after flash
chromatography (hexane–acetone 7 : 3 to hexane–acetone–
methanol 7 : 3 : 1) followed by crystallization from EtOH in
60% yield according to the above general procedure; mp 145–
157ꢀC. IR: CH 3051, 2964, 2518, 2378, C¼¼O 1695, C¼¼C þ
C¼¼N 1608, 1588, 1544, 1492 cmꢁ1. UV kmax (log e): 210
(4.35), 246 (4.46), 338 (3.88). 1H NMR (CDCl3): d 1.47 (t,
3H, J ¼ 7.2, CH3), 3.50 (q, 2H, J ¼ 7.5, NCH2), 5.44 (s, 2H,
OCH2), 7.13-8.86 (m, 12H, ArAH), 11.50 (bs, NH). 13C NMR
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(CDCl3): 11.00, 48.21, 66.01, 103.06, 109.51, 124.77, 126.43,
128.07, 128.14, 128.50, 130.44, 131.97, 135.93, 136.31,
145.58, 147.39, 148.99, 152.64, 162.13. Anal. Calcd. for
C22H20N4O2: C 70.95; H 5.41; N 15.04. Found: C 70.68; H
5.33; N 15.22. HRMS Calcd. for C22H21N4O2 (MþH)þ
373.16645. Found: 373.16605.
Method C. A mixture of 2a (0.2 g, 0.8 mmol), 3-amino-4-
pyrazol carboxamide (3e; 0.1 g, 0.8 mmol), and ethanol (3.8
mL) with concentrated HCl (0. 1 mL) was heated in a vial at
50ꢀC for 24 hrs. A solid precipitated during the heating. The
mixture was cooled down, the precipitate was filtered off to
give 0.17 g of yellow crystals (66%); mp 233–237ꢀC.
N-Ethyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide
(10). This compound was obtained after crystallization from
EtOH in 72% yield according to the above general procedure;
mp 105–108ꢀC. IR: CH 3051, 2973, C¼¼O 1646, C¼¼C þ
C¼¼N 1600, 1537, 1393 cmꢁ1. UV kmax (log e): 204 (4.33),
7-[3-(Ethylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-car-
boxamide (20). Using Method A described for the preparation
of 7-[3-[acetyl(ethyl)amino]phenyl]pyrazolo[1,5-a]pyrimidin-3-
carboxamide (19), compound 20 was obtained in 60% yield; mp
193–203ꢀC. IR: NH 3366, 3305, 3116, CH 2950, C¼¼O 1666,
C¼¼C þ C¼¼N 1626, 1543, 1513, 1472 cmꢁ1. UV kmax (log e):
206 (4.07), 246 (4.15), 350 (3.81). 1H NMR (DMSO): d 1.20 (t,
3H, J ¼ 7.1, CH3), 3.10 (q, 2H, J ¼ 7.1, CH2), 5.90 (t, 1H, J ¼
5.3, NH), 6.80-7.38 (m, 5H, ArAH), 7.50 (s, 1H, CONH2), 7.63
(s, 1H, CONH2), 8.59 (s, 1H, H-2), 8.81 (d, 1H, J ¼ 4.5, H-5).
13C NMR (DMSO): 14.21, 37.22, 105.17, 108.77, 112.55,
114.79, 116.61, 129.06, 130.45, 145.60, 146.80, 148.18, 148.88,
151.77, 162.64. Anal. Calcd. for C15H15N5O: C 64.04; H 5.37; N
24.90. Found: C 63.87; H 5.22; N 25.34. HRMS Calcd. for
C15H16N5O (MþH)þ 282.13549. Found: 282.13510.
1
234 (4.61), 350 (3.55). H NMR (DMSO): d 1.04 (t, 3H, J ¼
7.1, CH3), 1.82 (s, 3H, CH3CO), 3.70 (q, 2H, J ¼7.1, NCH2),
6.84 (d, 1H, J ¼ 2.2, H-3), 7.31 (d, 1H, J ¼ 4.3, H-6), 7.53
(d, 1H, J ¼ 7.9, H-40 or H-60), 7.67 (t, 1H, J ¼ 7.9, H-50),
8.07 (m, 1H, H-20), 8.13 (d, 1H, J ¼ 7.9, H-40 or H-60), 8.27
(d, 1H, J ¼ 2.2, H-2), 8.62 (d, 1H, J ¼ 4.3, H-5). 13C NMR
(DMSO): 12.90, 22.64, 43.07, 96.61, 107.85, 129.16, 129.67,
130.61, 131.79, 142.56, 144.46, 144.50, 149.34, 149.48,
170.03. Anal. Calcd. for C16H16N4O: C 68.55; H 5.75; N
19.99. Found: C 68.46; H 5.90; N 20.16. HRMS Calcd. for
C16H17N4O (MþH)þ 281.14024. Found: 281.13962.
7-(3-(N-Ethylacetamido)phenyl)pyrazolo[1,5-a]pyrimidine-
3-carboxylic acid (9). A mixture of N-[(2E)-3-[3-(dimethyla-
N-Ethyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)amine
(13). This compound was obtained after crystallization from EtOH
in 66% yield according to the above general procedure; mp 185–
190ꢀC. IR: CH 3062, 2913, 2661, 2483, C¼¼C þ C¼¼N 1606, 1580,
1538, 1452 cmꢁ1. UV kmax (log e): 204 (4.08), 232 (4.53), 352
mino)prop-2-enoyl]phenyl]-N-ethylacetamide (2a,
mmol), 3-amino-4-pyrazolecarboxylic acid (3d; 0.5 g,
1
g,
4
4
mmol), acetic acid (20 mL) was stirred at 50ꢀC for 24 hrs.
The mixture was evaporated, the residue was dissolved in
CH2Cl2 and extracted with 10% solution of Na2CO3 (5 ꢂ 8
mL). Insoluble particles were filtered off from the collected
aqueous portions and the clear solution was acidified with ace-
tic acid. Then the solution was extracted with CH2Cl2 (10 ꢂ
15 mL) and the extract was dried with MgSO4. The residue af-
ter evaporation was triturated with water and the insoluble por-
tion was filtered off to give 0.3 g (48%); mp 195–200ꢀC
(decomp.). IR: NH 3293, CH 2973, 2934, C¼¼O 1652, 1575,
1544, C¼¼C þ C¼¼N 1402, CO 1299 cmꢁ1. UV kmax (log e):
206 (4.11), 236 (4.33), 352 (3.56). 1H NMR (250 MHz,
DMSO): 1.05 (t, 3H, J ¼ 7.1, NCH2CH3), 2.08 (s, 3H,
COCH3), 3.72 (q, 2H, J ¼ 7.1, CH2), 7.31 (d, 1H, J ¼ 4.4, H-
6), 7.54 (d, 1H, J ¼ 7.6, H-40 or H-60), 7.67 (d, 1H, J ¼ 7.6,
H-50), 8.01 (m, 1H, H-20), 8.11 (d, 1H, J ¼ 7.6, H-40 or H-60),
8.34 (s, 1H, H-2), 8.65 (d, 1H, J ¼ 4.4, H-5). 13C NMR
(DMSO): 12.93, 22.65, 43.55, 107.78, 111.84, 128.59, 129.17,
129.67, 130.67, 131.81, 142.60, 145.00, 146.92, 147.06,
150.34, 165.72, 174.69. HRMS Calcd. for C17H17N4O3
(MþH)þ 325.13007. Found: 325.129469.
1
(3.62). H NMR (DMSO): d 1.27 (t, 3H, J ¼ 7.2, CH3), 3.37 (q,
2H, J ¼ 7.2, CH2), 6.85 (d, 1H, J ¼ 2.4, H-3), 7.25 (d, 1H, J ¼ 4.4,
H-6), 7.46 (d, 1H, J ¼ 7.3, H-40 or H-60), 7.61 (t, 1H, J ¼ 7.9, H-
50), 7.85 (d, 1H, J ¼ 7.3, H-40 or H-60), 7.97 (m, 1H, H-20), 8,28 (d,
1H, J ¼ 2.4, H-2), 8.64 (d, 1H, J ¼ 4.4, H-5), 11.75 (bs, NH). 13C
NMR (DMSO): 12.07, 42.96, 96.60, 107.75, 128.33, 129.24,
129.70, 130.33, 131.72, 142.72, 144.50, 144.94, 149.30, 149.54.
Anal. Calcd. for C14H14N4: C 70.57; H 5.92; N 23.51. Found: C
70.21; H 5.66; N 23.04. HRMS Calcd. for C14H15N4 (MþH)þ
239.12967. Found: 239.12918.
7-(3-(N-Ethylacetamido)phenyl)pyrazolo[1,5-a]pyrimidine-
3-carboxamide (19).
Method A. A mixture of compound 15 (1 g, 2.8 mmol) and
ethanol saturated with ammonia (10 mL) was heated in a pres-
sure tube at 100ꢀC for 5 days (TLC; toluene–ethanol–dioxane–
ammonia 5 : 2 : 4 : 1). The residue after evaporation was puri-
fied by flash chromatography (hexane–acetone, 7 : 3) to give
0.65 g of crude compound 19 and its crystallization (EtOH)
provided 0.45 g (50%) of yellowish crystals; mp 233–237ꢀC.
IR: NH 3394, 3121, CH 2984, C¼¼O 1652, C¼¼C þ C¼¼N
1622, 1597, 1544, 1482 cmꢁ1. UV kmax (log e): 206 (4.49),
7-(3-(N-Ethylamino)phenyl)pyrazolo[1,5-a]pyrimidine-3-
carboxylic acid (12). A mixture of N-[(2E)-3-[3-(dimethylami-
no)prop-2-enoyl]phenyl]-N-ethylformamide (2a) (2e, 0.25 g, 1
mmol), 3-amino-4-pyrazolecarboxylic acid (3d; 0.13 g, 1
mmol), formic acid (4 mL) was stirred at 75ꢀC for 16 hrs. The
mixture was evaporated and the residue was stirred with concen-
trated hydrochloric acid (3 mL) at 50ꢀC for 15 min. The residue
after evaporation was dissolved in water (10 mL), alkalized with
10% NaOH and extracted with diethyl ether (2 ꢂ 5 mL). The
extract was dried with MgSO4 and the residue after evaporation
containing according to TLC pure product of decarboxylation 13
(50 mg, 21%). The aqueous layer was neutralized with acetic
acid and extracted with dichloromethane (3 ꢂ 10 mL). The
extract was washed with water and dried with MgSO4. The resi-
due after evaporation was triturated with water and the insoluble
1
234 (4.51), 350 (3.82). H NMR (DMSO): d 1.06 (t, 3H, J ¼
7.2, NCH2CH3), 1.85 (s, 3H, CH3CO), 3.72 (q, 2H, J ¼ 7.2,
CH2), 7.54-8.20 (m, 7H, 5 ꢂ ArAH, 1 ꢂ CONH2), 8.61 (s,
1H, H-2), 8.86 (d, 1H, J ¼ 4.5, H-5). 13C NMR (DMSO):
12.91, 22.67, 43.37, 105.49, 109.32, 128.81, 129.43, 129.75,
130.11, 131.12, 142.63, 145.73, 146.09, 147.53, 151.86,
162.54, 169.70. UV kmax (log e): 206 (4.49), 234 (4.51), 350
(3.82). Anal. Calcd. for C17H17N5O2: C 63.15; H 5.30; N
21.66. Found: C 63.38; H 5.48; N 21.99. HRMS Calcd. for
C17H18N5O2 (MþH)þ 324.14605. Found: 324.14551.
Method B. The procedure is similar as Method (A), only 0.2 g
of MgBr2 was added and the mixture was heated for 1 day to pro-
vide after chromatography 38% of 19.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Synthesis of Some Impurities and/or Degradation Products of Zaleplon
283
[4] Dusza, J. P.; Tomcufcik, A. S.; Albright, J. D.; (American
Cyanamide), US 4,626,538 (1985); Chem Abstr 1986, 105, 72777.
[5] Thurajrajan, P.; (American Cyanamide), US 5,714,607
(1995); Chem Abstr 1998, 128, 154095.
portion was filtered off to provide 0.19 g (64%) of yellowish
crystals; mp 198–206ꢀC (decomp.). IR: CH 2981, 2941, C¼¼O
1667, 1652, NH 1538, CO 1231 cmꢁ1. UV kmax (log e): 204
(4.35), 236 (4.43), 352 (3.40). 1H NMR (250 MHz, DMSO):
1.18 (t, 3H, J ¼ 7.2, NCH2CH3), 3.07 (q, 2H, J ¼ 7.2, CH2),
6.78 (d, 1H, J ¼ 4.4, H-6), 7.14-7.35 (m, 4H, arom. H), 8.57 (s,
1H, H-2), 8.78 (d, 1H, J ¼ 4.4, H-5). 13C NMR (DMSO): 14.23,
37.99, 109.22, 112.57, 114.69, 114.97, 116.62, 129.02, 130.17,
130.61, 147.01, 147.97, 152.40, 163.23, 173.05. HRMS Calcd.
for C15H14N4O3 (MþH)þ 298.106590. Found: 298.11893.
[6] Korycinska, M.; Stawinski, T.; Wieczorek, M.; (Adamed),
WO 95,456 (2003); Chem Abstr 2003, 139, 381506.
´
[7] Korodi, F.; Feher, E.; Magyar, E.; (TEVA Pharmaceuticals),
WO 100828 (2002); Chem Abstr 2002, 138, 24725.
´
[8] Radl, S. (Zentiva), WO 37,824 (2004); Chem Abstr 2004,
143, 43894.
[9] Bharathi, C.; Prabahar, K. J.; Prasad, C. S.; Karavana, K.
M.; Magesh, S.; Handa, V. K.; Nadala, R.; Naidu, A. J Pharm Biomed
Anal 2007, 44, 101.
Acknowledgments. This work was a part of the Diploma work
´
of Michaela Blahovcova, which was supported by Zentiva
Prague.
´ ´ ´ ´ˇ
[10] Radl, S.; Blahovcova, M.; Tkadlecova, M.; Havlıcek, J.
Heterocycles, to appear.
[11] Howe, R. K.; Bolluyt, S. C. J Org Chem 1969, 34, 1713.
[12] Cusack, N. J.; Shaw, G.; Litchfield, G. J. J Chem Soc C
1971, 1501.
[13] Guo, Z.; Dowdy, E. D.; Li, W.-S.; Polniaszek, R.; Delaney,
E. Tetrahedron Lett 2001, 42, 1843.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet