Reinvestigation of the synthesis of ketanserin (5) and its hydrochloride salt (5.HCl) via 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) or dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1)

Article abstract of DOI:10.1002/jhet.1897

The synthesis of ketanserin (5) and its hydrochloride salt (5.HCl) using respectively equimolar amounts of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) with 4-(parafluorobenzoyl)piperidine (3) and dihydro-5H-oxazole(2,3-b) quinazolin-5-one (1) with hydrochloride salt of 4-(parafluorobenzoyl)piperidine (3.HCl) is reinvestigated. The one-pot reaction of ethyl-2-aminobenzoate with ethyl chloroformate and ethanol amine has afforded 3-(2-chloroethyl)-2,4-(1H,3H) -quinazolinedione (2) (86%) that was then refluxed with 4-(parafluorobenzoyl) piperidine (3) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin (87%). In another attempt, a very pure hydrochloride salt of ketanserin (5.HCl) was synthesized using equimolar amounts of dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1) and hydrochloride salt of 4-(parafluorobenzoyl)piperidine (3.HCl) by a solvent-less fusion method. Thus, under optimized conditions, 180°C and a reaction time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in chloroform but were transformed afterwards over time (2 h) to white precipitates (5.HCl) suspended in chloroform with a yield of 72%.

Full text of DOI:10.1002/jhet.1897

Month 2013 Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt
(5.HCl) via 3-(2-Chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) or
Dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1)
*
Hossein Fakhraian and Mehdi Heydary
Department of Chemistry, Imam Hossein University, Tehran, Iran
*
E-mail: fakhraian@yahoo.com
Received September 1, 2012
DOI 10.1002/jhet.1897
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
H NCH CH OH
2
2
2
O
CH CH Cl
OC
H
+
2
2
2
5
CHCl
N
3
ClC OC H
2 5
4h, 150 C
50 C, 30 min
NH
2
N
H
O
2
O
H
N
O
CH CH Cl
O
C
2
2
N
O
C
Na CO , CH COC H
2 5
2
3
3
+
+
HN
F
N
F
N
Reflux 24 h
N
H
O
3
5
2
O
HCl
O
H
N
O
N
O
O
C
180 o
30 min
C
HCl
CHCl3
O
?
+
F
HN
N
C
F
N
N
2 h, RT
3.HCl
5.HCl
1
O
glassy orange solid
mp = 225-232 o
C
The synthesis of ketanserin (5) and its hydrochloride salt (5.HCl) using respectively equimolar amounts
of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) with 4-(parafluorobenzoyl)piperidine (3) and dihydro-5H-
oxazole(2,3-b)quinazolin-5-one (1) with hydrochloride salt of 4-(parafluorobenzoyl)piperidine (3.HCl) is
reinvestigated. The one-pot reaction of ethyl-2-aminobenzoate with ethyl chloroformate and ethanol amine has
afforded 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) (86%) that was then refluxed with 4-(parafluoro-
benzoyl)piperidine (3) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin
(87%). In another attempt, a very pure hydrochloride salt of ketanserin (5.HCl) was synthesized using equimolar
amounts of dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1) and hydrochloride salt of 4-(parafluorobenzoyl)
piperidine (3.HCl) by a solvent-less fusion method. Thus, under optimized conditions, 180ꢀC and a reaction
time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in
chloroform but were transformed afterwards over time (2 h) to white precipitates (5.HCl) suspended in
chloroform with a yield of 72%.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
low yield, approximately 20%.[7,8] Another approach
consists of the reaction of 11COCl2 with 4 for preparing
11C-labeled ketanserin.[9]
Ketanserin (5), a drug with affinity for multiple G pro-
tein-coupled receptors, especially serotonin receptors, was
discovered at Janssen Pharmaceutical in 1980 and classi-
fied as an antihypertensive by the World Health Organiza-
tion. It has been used to reverse hypertension caused by
protamine (which, in turn, was administered to reverse
the effects of heparin overdose) and in cardiac surgery.
[1,2] Tritium (3H) radioactively labeled 5 was used as a
radioligand for the serotonin 5-HT2A receptor, for example,
in receptor binding assays and autoradiography.[3–6] This
radiolabeling enables the study of the serotonin-2A recep-
tor distribution in the human brain.
There are different methods for the preparation of 5
(Scheme 1).[7–11] The earliest one consists of reacting
3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) with
4-(parafluorobenzoyl)piperidine (3) in the presence of
Na2CO3 in a solvent such as isobutyl methyl ketone.
Following this method, the product 5 was obtained in a
Another process using equimolar quantities of 2,3-
dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1) and 3 for
preparation of 5 has been reported.[11,12] The reaction
of 1 with 3 was carried out in solvent-less conditions
by mixing the two reagents in powder form and heating
the mixture at 100ꢀC until fusion takes place. Maintai-
ning this temperature for a certain time has enabled the
reaction to go to completion. The reaction product was
in the form of a solid microcrystalline mass, from which
the product was obtained with a high degree of purity by
dissolving it in a solvent followed by recrystallization.
Another approach is to carry out the reaction in an inert
solvent, such as toluene, in the presence of a small quan-
tity of acid acting as a catalyst. In both cases, the prod-
uct was formed in high yields.
Two reagents (1 and the hydrochloride salt of 3) used in
the synthesizing procedure are known compounds and
© 2013 HeteroCorporation

H. Fakhraian and M. Heydary
Vol 000
Scheme 1
RESULTS AND DISCUSSION
H
N
N
O
O
We have firstly tried the synthesis of 2 via a three-step
method starting with ethyl 2-aminobenzoate (Scheme 2,
experimental part).
O
OR
Cl
N
N
The first step of the reaction was very exothermic
accompanied by rapid apparition of white precipitate soluble
in 1-propanol and dichloromethane and insoluble in chloro-
form. This reaction was performed under different reaction
conditions (solvent-less or in the presence of chloroform, at
RT or at 50ꢀC, at different reactant addition order). Under
solvent-less condition and using 110mol% of ethyl 2-chlor-
oformate, the apparition of white precipitate was instanta-
neous preventing the stirring of the reaction mixture, and
the yield was ~50%. The presence of a solvent in the reaction
medium is necessary because of the exothermic nature of the
reaction and volatility of ethyl chloroformate (bp 93ꢀC) caus-
ing increase of yield to 68%. Order of reactant addition does
not affect the yield of the product. GC–MS analysis of the
product and the presence of fragment with m/z of 238, 165,
and 119 attributed respectively to the MH+, M À COOEt,
and M À COOEt&OEt was conformed to the structure of
ethyl (2-ethoxycarbonyl)phenylcarbamate.
1
O
2
+
O
C
HN
F
3
H
N
O
O
C
F
N
N
5
O
COCl2
NHR
O
R
N
C
F
N
In the second step, dropwise addition of 2-aminoethanol
(500mol%) to ethyl (2-ethoxycarbonyl)phenylcarbamate
dissolved in chloroform caused initially apparition of white
vapor dissipated after a few minutes. Heating the reaction
mixture at 150ꢀC for 4 h allowing chloroform to be evaporated
from the reaction medium afforded 3-(2-hydroxyethyl)-2,4-
(1H,3H)-quinazolinedione as white precipitates in the reaction
medium at RT with a yield of 68%. GC–MS analysis of the
product and the presence of fragment with m/z of 207, 189,
163, and 146 attributed respectively to the M, M À OH, M À
CH2CH2OH, and M À NCH2CH2OH, and 1H-NMR and
13C-NMR spectra were conformed to the structure of ethyl
3-(2-ethoxyethyl)-2,4-(1H,3H)-quinazolinedione.
4
O
commercially available, although they can be prepared by
the methods described in the literature.[12–16]
Compound 2 is not commercial and should be prepared.
There are different reports concerning the preparation of
quinazolin-2,4(1H,3H)-diones.[17–19]
In this contribution, we propose a one-pot method for
high-yield preparation of 3-(2-chloroethyl)-2,4-(1H,3H)-
quinazolinedione and reinvestigate the synthesis of ketan-
serin and its hydrochloride salt via dihydro-5H-oxazole
(2,3-b)quinazolin-5-one or 3-(2-chloroethyl)-2,4-(1H,3H)-
quinazolinedione.
Scheme 2
O
O
OC2H5
OC2H5
OC2H5
O
CHCl3
OC2H5
Cl
O
NH2
N
50 C, 30 min
H
H2NCH2CH2OH
4h in 150 C
O
O
CH2CH2OH
CH2CH2Cl
N
N
SOCl2
Reflux, 4h
O
N
H
N
H
O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Ketanserin and its Hydrochloride Salt
In the last step, ethyl 3-(2-ethoxyethyl)-2,4-(1H,3H)-
quinazolinedione was dissolved in chloroform prior to
the dropwise addition of SOCl2 (200 mol%). After addi-
tion of SOCl2 and 30 min of heating, a white precipitate
appeared and disappeared after a few hours. Finally, after
24 h at reflux temperature, the product appears as a white
precipitate at the bottom of the flask with a yield of 78%.
GC–MS analysis of the product and the presence of
fragment with m/z of 188 and 146 attributed respectively
stirring the reaction mixture for 0.5 h at 50ꢀC, finally addi-
tion of 500 mol% of 2-aminoethanol (as reactant and sol-
vent with bp of 170ꢀC), and continuing the reaction
during 4 h at 150ꢀC afforded ethyl 3-(2-chloroethyl)-2,4-
(1H,3H)-quinazolinedione (2) with a yield of 87%. The
overall yield of the precedent three-step method was 36%
(Scheme 4).
We first tried to prepare 5 from the reaction of 2 with the
free base of 3. Only the hydrochloride salt of 3 was com-
mercially available, and it had to be transformed into the
free base. An aqueous solution of NaOH caused hydrolysis
of the hydrochloride salt of 3 and substitution of the fluo-
rine atom by a hydroxyl group. Using a methanolic solu-
tion of NaOH and Na2CO3 afforded the free base of 3
with a yield of 48% and 82%, respectively. When an aque-
ous solution of 32% ammoniac was used, the free base of 3
was obtained with a yield of 63%.
1
to M À Cl and M À NCH2CH2Cl, and H-NMR and 13C-
NMR spectra were conformed to the structure of ethyl
3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (2).
In some of our experiment, in the second step, conjoint
presence of ethyl 3-(2-ethoxyethyl)-2,4-(1H,3H)-quinazo-
linedione and ethyl 3-(2-chloroethyl)-2,4-(1H,3H)-quina-
zolinedione (2) has been observed. We have expected the
presence of minor amount of ethyl chloroformate with
the product of the first step that cause chlorination of 2-
aminoethanol [before cyclization reaction with ethyl (2-
ethoxycarbonyl)phenylcarbamate] or chlorination of the
product [after cyclization reaction with ethyl (2-ethoxycar-
bonyl)phenylcarbamate] in the second step. So, we have
tried a one-pot procedure in which ethyl chloroformate
was used as the reactant of the first step and chlorinating
agent for both 2-aminoethanol and ethyl 3-(2-ethox-
yethyl)-2,4-(1H,3H)-quinazolinedione (Scheme 3).
The preparation of 5 was accomplished with a yield of
86% via refluxing the mixture of 2, the free base of 3,
sodium carbonate, and ethyl methyl ketone for 24 h. The
previous reporting yield was 20%.[7]
Another method for the preparation of 5 was to use 1 as
reactant. Fusion of the powder mixture of the free base of 3
with 1 at 110ꢀC afforded a yellow solid with a yield of 85%
and an mp of 200–205ꢀC. The resulting product was not pure
and was recrystallized to obtain pure 5 (mp = 235–240ꢀC).
In another attempt, 5 was synthesized from the solvent-
less reaction by fusion of the powder mixture of 1 (mp =
160–163ꢀC) and the hydrochloride salt of 3 (mp = 222–
224ꢀC). Heating at 150ꢀC for 25 min do not affect the
powder mixture. Above 160ꢀC, the melting began and was
completed after 10min, forming an orange compound. The
mixture was solidified at RT (with an mp of 225–230ꢀC)
and dissolved in chloroform. The clear solution of orange
solid in chloroform was transformed to a turbid solution after
approximately 30 min because of the precipitation of a white
precipitate, the amount of which increased over 2 h (Fig. 1).
After filtering, washing with chloroform, and drying the
precipitate, the hydrochloride salt of 5 was obtained with a
purity over 95%. Using different temperatures and reaction
times afforded different yields of the hydrochloride salt
of 5 (Table 1). Under optimized conditions, the target
compound was obtained with a yield of 72% at 180ꢀC with
a total reaction time of 30min.
Thus, dropwise addition of ethyl 2-aminobenzoate to
250 mol% of ethyl chloroformate dissolved in chloroform,
Scheme 3
H2NCH2CH2OH
O
O
OC2H5
OC2H5
Cl
OC2H5
O
N
O
CH2CH2Cl
O
N
H
H2NCH2CH2Cl
N
H
O
Cl
OC2H5
O
O
CH2CH2OH
OC2H5
OC2H5
H2NCH2CH2OH
N
The advantages of this method compared with those
reported previously is the direct use of the hydrochloride
O
O
N
N
H
H
Scheme 4
O
O
O
CH2CH2Cl
Cl
N
OC2H5
OC2H5
CHCl3
50 C, 30 min
H2NCH2CH2OH
4h in 150 C
NH2
N
H
O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Fakhraian and M. Heydary
Vol 000
salt of 3 and obtaining the pure hydrochloride salt of 5
without the need of further recrystallization.
carbonyl carbon (C9 or C7) in the tartaric salt of 5 were
not observed. The chemical shift of the fluorine atom was
decreased (in absolute value) between 3 and 5 and their
hydrochloride salt forms.
The transformation of the orange solid to the hydrochlo-
ride salt of 5 does not take place in DMSO, as it does in
chloroform, and after several days at RT, only small
amounts of the hydrochloride salt of 5 were observed.
The nature of this orange solid is ambiguous, and GC–
MS analysis of the solution in chloroform showed two
reactants (1 and 3) with the same retention time and mass
spectroscopic pattern. It can be hypothesized that the or-
ange solid product is due to weak intermolecular binding
between 1 and the hydrochloride salt of 3 and is the major
cause that afforded the hydrochloride salt of 5 in chloro-
form by an unknown mechanism.
In summary, a one-pot scalable procedure was proposed
for the preparation of 3-(2-chloroethyl)-2,4-(1H,3H)-qui-
nazolinedione (2) via very accessible compound as ethyl
2-aminobenzoate, ethyl chloroform, and ethanol amine
with a yield of 87%. The preparation of 5 was accom-
plished with a yield of 86% via refluxing the mixture of
2, the free base of 3, sodium carbonate, and ethyl methyl
ketone for 24 h. The fusion reaction of 1 with the hydro-
chloride salt of 3 afforded a very pure hydrochloride salt
of 5 without the need for a further recrystallization proce-
dure; however, at higher temperatures and with 10% lower
yield than in previous reports were observed concerning
the preparation of free base of 5. An interesting observation
is the initial solubility of the orange solid, formed from the
reaction of 1 with the hydrochloride salt of 3, in chloro-
form and the subsequent precipitation of the pure hydro-
chloride salt of 5.
The 13C-NMR and 19F-NMR characteristics of 3 and 5,
the hydrochloride salts of 3 and 5 (in DMSO-d6), and the
tartaric salt of 5 (in D2O) are outlined in Table 2.
The chemical shifts of one of the carbons of the piperi-
dine ring in the hydrochloride salt of 3 and 5 and the
EXPERIMENTAL
NMR spectra were obtained on a Bruker DPX-250 instrument
(235.3 MHz for 19F and 62.5 MHz for 13C), and CDCl3, D2O, and
DMSO-d6 were used as solvents; chemical shifts are reported in d
(ppm) from TMS for 13C and CFCl3 for 19F. Electronic ionization
GC–MS spectra were recorded on a Varian (SATURN 4D) spec-
trometer with a capillary column (DB-5MS, 0.1 mm, 30 m  0.250
mm). Only m/z values having intensities of more than 10% are
given, and retention times are reported using temperature
programming (100–250ꢀC, 10ꢀC/min) with an He flow rate of
10 mL/min. HPLC analyses were performed on a Knauer EA
4300F equipped with a UV detector, model 2600, and a C18
column (250 Â 4.6 mm) with an eluent flow rate of 1 mL/min.
Melting points were obtained on a Mettler FP61 apparatus.
2,3-Dihydro-5H-oxazole(2,3-b)quinazolin-5-one (95%) was pur-
chased from Aldrich company.
Figure 1. Different steps in the formation of the hydrochloride salt of 5 via
fusion of a powder mixture of 1 and the hydrochloride salt of 3. (a) Before heat-
ing, (b) After heating above 160ꢀC, (c) Immediately after dissolution in CH3Cl
at RT, and (d) 2 h after dissolution in CH3Cl at RT. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 1
Preparation of 5 from the equimolar fusion reaction of 1 and the hydrochloride salt of 3 at 0.01 M scale under different oven temperatures and reaction times.
Yield
Experiment
Temperature (ꢀC)
Melting time (min)
Reaction time (min)
(%)
1
2
3
4
5
6
7
8
9
240
240
220
220
200
200
200
200
180
180
160
3
3
4
4
6
6
7
7
6
12
8
52
59
63
58
39
55
34
53
60
72
62
15
10
20
10
27
18
20
50
10
10
25
10
11
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Ketanserin and its Hydrochloride Salt
Table 2
13C-NMR and 19F-NMR characteristics of 3, 5, hydrochloride salts of 3 and 5 (in DMSO-d6) and tartaric salt of 5 (in D2O).
13C
19F
Compound
d (ppm)
d (ppm)
À105.6
À104.7
À106.5
3
28.9, 42.3, 115.7 (C8—F), 116.0 (C8—F), 131.3 (C9,13—F), 131.4 (C9,13—F),
131.6 (C10,12—F), 131.7 (C10,12—F), 163.1 (C11—F), 167.1 (C11—F), 199.9
28.4, 39.9, 42.6, 115.6 (C8—F), 115.9 (C8—F), 131.1 (C9,13—F), 131.2 (C9,13—F),
132.1 (C10,12—F), 132.2 (C10,12—F), 162.9 (C11—F), 166.9 (C11—F), 200.9 (C7)
28.4, 37.4, 42.5, 52.6, 55.1, 113.6, 115.0, 115.5 (C22—F), 115.9 (C22—F), 122.4,
127.3, 131.0 (C23,27—F), 131.1 (C23,27—F), 132.2 (C24,26—F), 132.3 (C24,26—F),
3.HCl
5
134.9, 139.3, 150.0, 161.8, 162.8 (C25—F), 166.8 (C25—F), 201.1(C21
)
5.HCl
25.6, 34.8, 51.3, 53.8, 113.9, 115.1, 115.7 (C22—F), 116.0 (C22—F), 122.5, 127.3,
131.2 (C23,27—F), 131.4 (C23,27—F), 131.7 (C24,26—F), 131.8 (C24,26—F), 135.1,
139.5, 150.3, 162.3, 163.1 (C25—F), 167.1 (C25—F), 199.1, 199.5
25.8, 35.5, 40.4, 52.5, 54.7, 72.6 (Tartarate), 113.3, 115.4, 115.8 (C22—F), 116.1
(C22—F), 123.9, 127.2, 130.0 (C23,27—F), 131.1 (C23,27—F), 131.3 (C24,26—F),
131.5 (C24,26—F), 136.1, 138.5, 151.6, 164.0 (C25—F), 164.4, 168.1 (C25—F),
176.0 (Tartarate), 202.9
À104.7
À104.7
5.C4H4O6
1
Three-step preparation of 3-(2-chloroethyl)-2,4-(1H,3H)-
quinazolinedione. In the first step, ethyl 2-aminobenzoate
(0.01 mol, 1.47 mL) was added dropwise to a 25-mL double-
necked flask equipped with magnetic stir bar and containing ethyl
chloroformate (0.011 mol, 1.05 mL) and chloroform (5mL).
The reaction was very exothermic, and after 15–20 s, white
precipitates were formed. After 5 min, the precipitates were
filtered and washed with ether to afford 1.6g (68%) of ethyl 2-
(ethoxycarbonyl)phenyl carbamate. mp = 175–178ꢀC. GC–MS:
retention time: 4.6 min (Tcol = 150ꢀC); m/z [intensity (%)]:166
(15), 165 (100), 120 (31), 119 (33).
127.8, 135.6, 139.7, 150.4, 162.4. H-NMR (DMSO-d6, d ppm):
3.7 (CH2), 3.9 (CH2), 7.1 (CH), 7.6 (CH), 7.9 (CH), 11.5 (NH).
One-pot preparation of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazo-
linedione. Ethyl 2-aminobenzoate (0.01 mol, 1.47 mL) was added
dropwise to a 25-mL double-necked flask equipped with magnetic
stir bar and containing ethyl chloroformate (0.025 mol, 2.4mL)
and chloroform (5 mL). The reaction was very exothermic, and
after 15–20 s, white precipitates were formed. The reaction mixture
was stirred at 50ꢀC for 30min after which ethanol amine
(0.05 mol, 3.1mL) was added dropwise, and the reaction mixture
was stirred at 150ꢀC for 4 h. White precipitates (form at RT) were
filtrated and washed with isopropanol affording 1.95 g (87%) of 3-
In the second step, the mixture of ethyl 2-(ethoxycarbonyl)phe-
nyl carbamate (0.001mol, 2.1 g), ethanol amine (0.05 mol,
3.1 mL), and chloroform (5mL) in a one-necked flask equipped
with magnetic stir bar was heated at 150ꢀC for 4 h. White precipi-
tates (form at RT) were filtrated and washed with isopropanol
affording 1.4 g (68%) of 3-(2-hydroxyethyl)quinazoline-2,4
(1H,3H)-dione. mp = 261–263ꢀC (lit.7 273.6ꢀC). GC–MS: retention
time: 5.1 min (Tcol =250ꢀC); (m/z) (%), 28 (24), 29 (12), 31 (24), 39
(12), 63 (24), 64 (14), 90 (22), 92 (18), 119 (50), 146 (95), 147 (17),
163 (81), 188 (32), 189 (100), 207 (64). 13C-NMR (DMSO-d6, d
ppm): 42.5, 58.2, 114.2, 115.4, 122.8, 127.7, 135.2, 139.7, 150.7,
(2-chloroethyl)quinazoline-2,4(1H,3H)-dione.
mp = 205–207ꢀC
(lit.7 215.3ꢀC).
Preparation of ketanserin (5). 3-(2-Chloroethyl)-2,4-(1H,3H)-
quinazolinedione (2) (0.002 mol, 0.45 g) and 4-(parafluorobenzoyl)
piperidine (3) (0.002 mol, 0.49 g), Na2CO3 (1.3 mol, 0.8 g), and
methyl ethyl ketone (8mL) were placed into a 50-mL one-necked
flask equipped with a magnetic stir bar. The mixture was stirred
and refluxed for 24 h after which the precipitates were appeared.
Water (50mL) was added to the mixture, and the precipitates were
filtrated, washed with water, and dried to afford 0.68 g (86%) of
ketanserin (lit.7 27%). mp=231–234ꢀC (lit.7,11 227–235ꢀC). 13C-
NMR (CDCl3, d ppm): 28.9, 37.9, 43.5, 53.1, 55.6, 114.1, 115.7,
116.1, 116.4, 122.7, 127.7, 131.5, 131.6, 132.7, 135.3, 140.1,
150.6, 162.3, 167, 201.6. 1H-NMR (DMSO-d6, d ppm): 1.5
(CH2), 2.1 (CH2), 2.5 (CH2), 3 (CH), 3.3 (CH2), 3.7 (CH), 7.2
(CH), 7.3 (CH), 7.6 (CH), 7.9 (CH), 8 (CH).
1
162.5. H-NMR (DMSO-d6, d ppm): 3.5 (CH2), 3.9 (CH2), 7.1
(CH), 7.6 (CH), 7.9 (CH), 11.2 (NH).
In the third step, the mixture of 3-(2-hydroxyethyl)quinazoline-
2,4(1H,3H)-dione (0.02 mol, 4.1g), chloroform (50 mL), and
SOCl2 (0.04 mol, 2.9 mL) was refluxed for 4 h. White precipitates
(at RT) were filtered and washed with chloroform to afford 3.2g
(78%) of 3-(2-chloroethyl)quinazoline-2,4(1H,3H)-dione (2) (lit.7
86%). mp= 196–198ꢀC (lit.7 215.3ꢀC). GC–MS: retention time:
4.1 min (Tcol =250ꢀC); (m/z) (%), 146 (59), 188 (100), 189 (22).
13C-NMR (DMSO-d6, d ppm): 41.1, 41,5, 113.9, 115.6, 123.1,
Preparation of ketanserin hydrochloride (5.HCl). Powders
of 2,3-dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1) (0.02 mol,
3.72 g) and hydrochloride salt of 4-(parafluorobenzoyl)
piperidine (3.HCl) (0.02 mol, 4.88 g) were mixed together and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Fakhraian and M. Heydary
Vol 000
[3] Pietzch, H. J.; Scheunemann, M.; Spies, H.; Brust, P.;
Johansen B. Forschungszent. Rossendorf, [ber] FZR 1996, (FZR-122),
31; Chem Abstr 1996, 125, 74599y.
[4] Scheunemann, M.; Pietzch, H. J.; Brust, P.; Wober, J.; Spies,
H.; Johansen, B. Forschungszent. Rossendorf, [ber] FZR 1996,
(FZR-122), 34; Chem Abstr 1996, 125, 58427k.
[5] Scheunemann, M.; Pietzch, H. J.; Spies, H.; Brust, P.;
Johansen, B. Forschungszent. Rossendorf, [ber] FZR 1996, (FZR-122),
44; Chem Abstr 1996, 125, 58428m.
[6] Janssen, C. G. M.; Lenoir, H. A. C.; Thijssen, J. B. A.; Knaeps,
A. G.; Verluyten, W. L. M.; Heykans, J. J. P. J Labelled Compd
Radiopharm 1988, 25(7), 783.
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94, 65718a.
[8] Vandenberk, J.; Kennis, L. E. J.; Van Der Aa, M.;
Van, Heertum, A. U.S. Patent 4,335,127; Chem Abstr 1982, 97,
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[9] Berridge, M.; Comar, D.; Crouzel, C.; Baron, J. C. J. Labelled
Compd Radiopharm 1983, 20(10), 73.
[10] Kennis, L. E. J.; J. Vandenberk, Boey, J. M.; Martens, J. C.; V.
Heertum, Albert H. M.; Janssen, M.; Awouter, F. Drug Dev Res 1986, 8
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[11] Signorini, R.; Verga, A. Eur Pat Appl EP 98499; Chem Abstr
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were placed into a 250-mL one-necked flask equipped with a 3-
cm magnetic stir bar. Fusion of the mixture started after stirring
at 180ꢀC for 10 min. The mixture was kept at 180ꢀC and stirred
for another 20 min. The initial white powders were transformed
into an orange liquid that solidified at RT as a glassy orange
solid (mp = 225–230ꢀC), dissolution of which in chloroform
(50 mL) was accompanied by the appearance of white precipitates
started after 30 min and continued for 2 h. The precipitates
were filtrated and washed with CHCl3 to afford 6.5 g of white
powder (72%) mp= 305–307ꢀC, HPLC: retention time= 3.3 min
(H2O/MeOH (75:25); 1 mL/min; detection at 220nm).
Preparation of the free base of 3. Hydrochloride salt of 4-
(parafluorobenzoyl)piperidine (3.HCl) (0.01 mol, 2.44 g) was
dissolved in methanol (50mL), and then Na2CO3 (0.02 mol,
2.10g) was added to the solution. The mixture was stirred for 4 h
at RT. After the evaporation of methanol, extraction with
chloroform, and evaporation of solvent, 1.7g of the free base of 3
(82%) was obtained. The same procedure using NaOH and an
aqueous solution of NH3 (32%) as a base afforded 1 and 1.3g,
respectively, of 3 (48% and 63%, respectively). mp = 109–114ꢀC.
GC–MS: retention time: 3.2min; m/z [intensity (%)]:78 (20), 79
(62), 84 (17), 123 (32), 207 (19), 208 (30).
[12] Sun, L.; Fang, Y. Chinese Patent CN 1,793,138; Chem Abstr
2006, 145, 167271 p.
[13] Gueyrard, D.; Leoni, O.; Palmieri, S.; Rollin, P. Tetrahedron:
asymmetry 2001, 12, 337.
[14] Willis, M.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L. Org
Lett, 2006, 8(22), 5089.
Preparation of ketanserin tartarate (5.C4H4O6). Dissolution of
5 (0.001 mol, 0.39 g) and tartaric acid (0.001 mol, 0.15 g) in ethanol
(60 mL) and evaporation of the solvent afforded quantitative yield
of ketanserin tartarate with an mp of 185–190ꢀC (Sigma-Aldrich
183–184ꢀC). The solubility of this salt in ethanol was 8 g/L.
[15] Eleftherios, P. P. J Heterocyclic Chem 1980, 17, 1553.
[16] Dou, G.-L.; Wang, M.-M.; Huang, Z.-B.; Shi, D. -Q. J
Heterocyclic Chem 2009, 46(4), 645.
REFERENCES AND NOTES
[17] El-Baih, F. E. M.; Bakari, S. B. A.; Hijaz, A. A. JKAU: Sci
2004, 16, 41.
[18] Dou, G.-L.; Wang, M.-M.; Huang, Z.-B.; Shi, D.-Q. Tetrahedron
2007, 63, 9764.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet