Synthesis of a series of carbon-14 labelled 4-aminoquinazolines and quinazolin-4 (3H)-ones

Article abstract of DOI:10.1002/jlcr.1658

4-Aminoquinazolines and quinazolin-4 (3H)-ones, both labelled with carbon-14 in the 4-position, were prepared from 2-aminobenzonitrile-[cyano- ¹⁴C] and 2-aminobenzoic acid-[carboxy -¹⁴C] or 2-amino- benzamide-[carboxy -¹⁴C

Full text of DOI:10.1002/jlcr.1658

Research Article
Received 14 February 2009,
Revised 7 June 2009,
Accepted 9 June 2009
Published online 17 July 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1658
Synthesis of a series of carbon-14 labelled
4-aminoquinazolines and quinazolin-4
(3H)-ones
Ã
Nader Saemian, Omid Khalili Arjomandi, and Gholamhossein Shirvani
4-Aminoquinazolines and quinazolin-4 (3H)-ones, both labelled with carbon-14 in the 4-position, were prepared from
2-aminobenzonitrile-[cyano-14C] and 2-aminobenzoic acid-[carboxy -14C] or 2-amino- benzamide-[carboxy -14C], respec-
tively, using rapid, one-pot procedures under microwave enhanced conditions.
Keywords: quinazolines; quinazolin-4-ones; microwave heating; 2-aminobenzamide; carbon-14
good yield.10,11 5 could then be converted to 4-aminoquinazo-
line-[4-14C] 1, by treatment with arylnitrile 6 in the presence of
Introduction
Quinazolines have been a rich source of biologically active
molecular entities and are related to wide family of
t-BuOK under microwave irradiation, in the absence of solvent.
Product 1 was obtained in good yield.12
a
compounds with well-known pharmacological properties.1–3
Among the different substitution patterns that are known,
4-aminoquinazolines and quinazolin-4 (3H)-ones are important
because of their potential biological and pharmaceutical
activities. 4-Aminoquinazolines are useful as fungicides and
anti-inflammatory, anti-cancer, anti-microbial and anti-hypertensive
agents.4,5 Quinazolin-4 (3H)-ones have also emerged as an
important class of nitrogen containing heterocyclic compounds
because of their pharmacological and therapeutic properties
and show anti-bacterial, anti-fungal, anti-malarial, anti-hypertensive,
activity. These compounds also show effects on the central
nervous system (CNS) and have sedative-hypotic and anti-
convulsant, anti-parkinsonism, anti-histaminic properties.6–8 To
further elucidate the mechanism of action and investigate the
pharmacokinetics and drug metabolism of these compounds,
the preparation of suitable metabolically stable carbon-14
labels were required.9 This paper reports the Synthesis of
Carbon-14 labelled 4-aminoquinazolines (1a, b, c) and quinazolin-
4 (3H)-ones (2a, b, c).
Our approach to the synthesis of quinazolin-4(3H)-ones-
[4-14C] 2a, b, c is shown in Scheme 2. 5 is converted to
2-aminobenzoic acid-[carboxy-14C] 6a by treatment with
aqueous base.13 A mixture of 6a and amine 7 and formic
acid 8 was then irradiated under microwave condition in the
absence of solvent or any dehydrating agents. In order to
control the reaction the irradiation was carried out in two stages
with a cooling time between them. In both cases however, to
ensure optimum yield of products, an excess of formic acid 8
had to be employed.14–16 On the other hand, using the known
17,18
Niementowski reaction,
with 6a under microwave irradiation, gave the desired product 2
the condensation of formamide 9
in a few minutes.
The conversion of 2-aminobenzonitrile-[cyano-14C]
5 to
2-aminobenzoic acid-[carboxy-14C] 6a by treatment with aqu-
eous base is a long procedure and the work up and collection of
2-aminobenzoic acid-[carboxy-14C] 6a from aqueous media is
very difficult. An improved process using 2-aminobenzamide-
[carboxy-14C] 6b instead of 6a was therefore developed. In this
route, 5 was converted to 6b using basic hydrogen peroxide in
DMSO in good yield (90%, 1 h).19 A mixture of 6b and
formamide 9, in the presence of N,N-dimethylacetamide,
NH
C
O
C
R
N
N
introduced as a fusion accelerator was irradiated under
microwave condition to give quinazolin-4 (3H)-ones (2a, b, c)
N
Ar
N
in good yield.
1a:(Ar: 2-thiophenyl)
b:(Ar: m-cyanophenyl)
c:(Ar: phenyl)
2a: (R= phenyl)
b: (R: 4-chlorophenyl)
c: (R: benzyl)
Radioisotope section/Nuclear Science Research School, Nuclear Science and
Technology Research Institute, P.O. Box. 11365-3486, Islamic Republic of Iran
Discussion
Our approach to the synthesis of 4-aminoquinazolines-[4-14C]
1a, b, c is shown in Scheme 1. 2-Aminobenzonitrile-[cyano-14C] 5
*Correspondence to: Nader Saemian, Radioisotope section/Nuclear Science
Research School, Nuclear Science and Technology Research Institute, P.O. Box.
11365-3486, Islamic Republic of Iran.
was derived from the reaction of 2-iodoaniline
4 with
potassium[14C] cyanide 2 and cuprous iodide 3 in hot DMF, in E-mail: nsaemian67@gmail.com
J. Label Compd. Radiopharm 2009, 52 453–456
Copyright r 2009 John Wiley & Sons, Ltd.

N. Saemian et al.
I
acetate, the combined organics washed three times with water,
dried over anhydrous MgSO4, filtered and the solvent carefully
evaporated. The crude product was purified by silica gel
chromatography using ethyl acetate:hexane (1:4) as eluant to
give 2-aminobenzonitrile [cyano-14C] (272 MBq, 354 mg) 5
(radiochemical yield: 85.5 %). (Rt: 2.3 min), 1H-NMR (CDCl3,
TMS): d7.4, d, 1H; d7.34, t, 1H; d6.74–6.78, m, 2H; d4.47,s, 2H, MS
(70 eV): m/z = 120 (M1).
Ba14CO3
K14CN
2
+
CuI
3
+
NH2
4
5
a
NH2
14C
14CN
NH2
b
N
Ar-CN
6
+
4-Amino-2-(2-thiophenyl)-quinazoline-[4-14C] 1a
N
Ar
1
A
mixture of 2-aminobenzonitrile-[cyano-14C] (76.84 MBq,
Scheme 1. (a) DMF and (b) KO-t-Bu, MW.
100 mg) 5, 2-thiophenenitrile (92 mg) 6a and potassium tert-
butoxide (10 mg) in a test tube was heated in a domestic
microwave oven until no starting materials were observed by
TLC(700 W, 1.5 min.). The crude reaction was purified by
crystallization from methanol to afford 1a (63.77 MBq, 160 mg,
83%). (Rt: 3.15 min),1H-NMR (CD3OD, TMS): d8.19, d, 1H; d8.14,d,
1H; d7.89, m, 2H; d7.68, d, 1H; d7.55, m, 1 H; d7.28, t, 1H., MS
(70 eV): m/z = 229 (M1).
14CO2H
b
R
NH2
+
+
HCO2H
7
a
8
NH2
6a
O
14C
R
14CN
NH2
N
4-Amino-2-(3-cyanophenyl)-quinazoline-[4-14C] 1b
N
2
1b was prepared according to the above-described procedure
by heating 5 (76.84 MBq, 100 mg) and 1,3-dicyanobenzene
(108 mg) 6b under microwave irradiation (700 W, 2 min, radio-
chemical yield: 80%). (Rt: 3.5 min),1H-NMR (Cl3CD, TMS): d8.84, s,
1H; d8.78,d, 1H; d7.95, d, 1H; d7.72–7.82, m, 3H; d7.52–7.61, m,
2H; d5.81, brs, 2H., MS (70 eV): m/z = 248 (M1).
5
O
14C
O
H
c
NH2
NH2
6b
NH
R
+
d
9
Scheme 2. (a) KOH/EtOH; (b) MW; (c) K2CO3, DMSO, H2O2 30%; (d) MW,
N,N-dimethylacetamide.
4-Amino-2-phenyl-quinazoline-[4-14C] 1c
1c was prepared according to the above-described procedure
by heating 5 (76.84 MBq, 100 mg) and benzonitrile (87 mg) 6c
under microwave irradiation(700 W, 2 min, radiochemical yield:
87%).(Rt: 3.05 min),1H-NMR (Cl3CD, TMS): d8.50, d, 2H; d7.98,m,
1H; d7.72–7.82, m, 2H; d7.42–7.57, m, 4H; d5.73, brs, 2H., MS
(70 eV): m/z = 223 (M1).
Experimental
Barium [14C]carbonate was converted to potassium [14C]cyanide
according to the standard procedure.20 IR spectra were recorded
on a Bruker FT-IR, Vector 22 instrument and the1H- NMR spectra
were recorded on a Varian unity plus 400 spectrometer
(400 MHz). HPLC: equipment consisted of: a waters 1525 Binary
HPLC pump, a waters 2487 Dual l absorbance detector, a
2-Aminobenzoic acid-[carboxyl-14 C] 6a
waters
Breeze
Data
processing
system,
Column: A mixture of 2-amino-benzonitrile-[cyano-14C] 5 (1500 mg,
m Bondapak18 (150 Â 4.6 mm) and 5 mm diameters and uv 1152.5 MBq) and potassium hydroxide (34.6 g) in Water(577 ml)
detection at l = 254 nm. The isocratic elution was used for was stirred and heated under reflux for 5 h affording a clear
chromatographic separation at room temperature. The eluent brown solution. After cooling to room temperature, the reaction
was CH3CN: H2O (60:40) with flow rate: 1 mL/min. Microwave mixture was neutralized with HCl(conc.) to pH = 3–4, when
irradiation was carried out in a national oven, model 5250 at precipitation occurred. The reaction mixture was extracted with
2450 MHz. All the experiments were performed in an efficient ethyl acetate (5 Â 300 ml). The organic phase was dried over
ventilated enclosure, in order to avoid exposure with vapors. Na2SO4, filtered and concentrated in vacuo affording 6a
Radioactivity was determined using a Beckman LS6500 liquid (1500 mg, 991.2 MBq) in 86% yield(Rt: 1.35 min), MS (70 eV):
scintillation spectrometer. Mass spectra were obtained on a m/z = 139 (M1).
Finnigan TSQ-70 instrument.
3-Phenyl-quinazolin-4-one-[4-14C] 2a
2-Amino-benzonitrile-[cyano-14C] 5
A mixture of 2-aminobenzoic acid-[carboxyl-14C] 6a (1370 mg,
Cuprous iodide 3 (815 mg) was ground finely and dried in the 905.29 MBq), formic acid 8 (690 mg) and aniline 7a (1210 mg)
reaction flask under high vacuum by heating with a hot air gun contained in a tall beaker was placed in the microwave oven
and cooled under nitrogen. Potassium [14C]cyanide (318 MBq, and the beaker was covered with a stemless funnel and
228 mg) 2 was added slurried in dry DMF (10 ml), followed by irradiated for 3 min at power 210 W. After about 5 min, as it
2-iodoaniline 4 (1718 mg). The mixture was heated at reflux, cooled to room temperature, the reaction mixture was irradiated
under nitrogen, for 10 h. On cooling a solution of potassium again for 4 min at 385 W. Then the reaction mixture was
cyanide (1.2 g) in water (50 ml) and ethyl acetate (20 ml) were dissolved in hot ethanol–water from which the product crystal-
added and the mixture stirred vigorously for 15 min. The layers lized. The product was recrystallized from 1M NaOH-ethanol
were separated, the aqueous thoroughly extracted with ethyl (2:5) to give (1600 mg, 651.81 MBq) of 2a (radiochemical
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J. Label Compd. Radiopharm 2009, 52 453–456

N. Saemian et al.
yield: 72%). (Rt: 2.5 min),1H-NMR (Cl3CD, TMS): d8.36, dd, the mixture and the organic phase was separated, dried over
1H; d8.14, s, 1H; d7.55–7.58, m, 2H; d7.26–7.45, m, 6H., MS anhydrous sodium sulfate, filtered and the solvent removed
(70 eV): m/z = 224 (M1).
under reduced pressure. The product was purified by silica gel
chromatography using chloroform:methanol (9:1) as eluant to
give 6b (998.64 MBq, 1500 mg). (Rt: 1.6 min), MS (70 eV):
m/z = 138 (M1).
3-(4-Chloro-phenyl)-quinazolin-4-one-[4-14C] 2b
2b was prepared according to the above-described procedure
by heating a mixture of 2-aminobenzoic acid-[carboxyl-14C] 6a
(1370 mg,905.29 MBq), formic acid 8 (690mg) and 4-chloro-
aniline 7b (1275 mg) under microwave irradiation (3 min at
Alternative procedures for preparation of (2a–c)-[4-14C]
210 W and 3 min at 385 W radiochemical yield: 68%).(Rt: 3.2 min), Method II
1H-NMR (Cl3CD, TMS): d8.38, dd, 1H; d8.10, s, 1H; d7.79–7.83,
3-Phenyl-quinazolin-4-one-[4-14C] 2a: A mixture of formanilide 9a
m, 2H; d7.35–7.59, m, 3H; d7.38–7.40, m, 2H., MS (70 eV):
(1.21 g, 10mmol), 2-amino-benzamide-[carboxy-14C] 6b (1360 mg,
905.43MBq ), and a few drops of N,N-dimethylacetamide
were heated under microwave irradiation(6 min at 385 W).
The resultant residue after crystallization from hot ethanol–
water gave 1842mg, 751.50MBq of 2a (radiochemical
yield: 83%). (Rt: 2.5 min),1H-NMR (Cl3CD, TMS): d8.36, dd, 1H;
d8.14, s, 1H; d7.55–7.58, m, 2H; d7.26–7.45, m, 6H., MS (70 eV):
m/z = 224 (M1).
m/z = 258 (M1).
3-benzyl-quinazolin-4-one-[4-14C] 2c
2c was prepared according to the above-described procedure
by heating a mixture of 2-aminobenzoic acid-[carboxyl-14C] 6a
(1370 mg,905.29 MBq), formic acid 8 (690 mg) and benzylamine
7c (1390 mg) under microwave irradiation (3 min at 210 W, 2 and
6 min at 385 W radiochemical yield: 65%). (Rt: 2.8 min),1H-NMR
(Cl3CD, TMS): d8.34, dd, 1H; d8.12, s, 1H; d7.70–7.78, m, 2H;
d7.52–7.61, m, 1; d7.33–7.37, m, 5H; d5.21, s, 2H, MS (70 eV):
m/z = 238 (M1).
3-(4-Chloro-phenyl)-quinazolin-4-one-[4-14C] 2b: 2b was pre-
pared according to the above-described procedure by heating a
mixture of 4-chloroformanilide 9b (1555 mg, 10 mmol), 2-amino-
benzamide-[carboxy-14C] 6b (1360 mg,905.43 MBq), and
a
few drops of N,N-dimethylacetamide under microwave irradia-
tion(6 min at 385 W, radiochemical yield: 79%). (Rt: 3.2 min),
1H-NMR (Cl3CD, TMS): d8.38, dd, 1H; d8.10, s, 1H; d7.79–7.83,
m, 2H; d7.35–7.59, m, 3H; d7.38–7.40, m, 2H., MS (70 eV):
m/z = 258 (M1).
3-benzyl-quinazolin-4-one-[4-14C] 2c: 2c was prepared accord-
ing to the above-described procedure by heating a mixture of
benzyl formamide 9c (1350 mg, 10 mmol), 2-amino-benzamide-
[carboxy-14C] 6b (1360 mg,905.43 MBq), and a few drops of N,N-
dimethylacetamide under microwave irradiation(6 min at 385 W,
radiochemical yield: 74%). (Rt: 2.8 min),1H-NMR (Cl3CD, TMS):
d8.34, dd, 1H; d8.12, s, 1H; d7.70–7.78, m, 2H; d7.52–7.61, m, 1;
d7.33–7.37, m, 5H; d5.21, s, 2H., MS (70 eV): m/z = 238 (M1).
Alternative procedures for preparation of (2a–c)-[4-14C]
Method I
3-Phenyl-quinazolin-4-one-[4-14C] 2a: A mixture of N-phenylfor-
mamide 9a (1.21 g, 10 mmol), 2-aminobenzoic acid-[car-
boxyl-14C] 6a (1370 mg,905.29 MBq), and a few drops of
N,N-dimethylacetamide were heated under microwave irradia-
tion (6 min at 385 W). The resultant residue after crystallization
from hot ethanol–water gave of 2a (1776 mg, 724.23 MBq)
(radiochemical yield: 80%). (Rt: 2.5 min), 1H-NMR (Cl3CD, TMS):
d8.36, dd, 1H; d8.14, s, 1H; d7.55–7.58, m, 2H; d7.26–7.45, m, 6H.,
MS (70 eV): m/z = 224 (M1).
3-(4-Chloro-phenyl)-quinazolin-4-one-[4-14C] 2b: 2b was
prepared according to the above-described procedure
by heating a mixture of 4-N-(4-chlorophenyl)formamide 9b
(1555 mg, 10 mmol), 2-aminobenzoic acid-[carboxyl-14C]
6a (1370 mg,905.29 MBq), and a few drops of N,N-dimethyl-
acetamide under microwave irradiation (6 min at 385 W,
radiochemical yield: 76%). (Rt: 3.2 min),1H-NMR (Cl3CD, TMS):
d8.38, dd, 1H; d8.10, s, 1H; d7.79À7.83, m, 2H; d7.35–7.59, m, 3H;
d7.38–7.40, m, 2H., MS (70 eV): m/z = 258 (M1).
Conclusion
In this paper, we have presented a convenient synthetic
pathway for labelling of a series of 4-amino- quinazolines and
quinazolin-4 (3H)-ones with carbon-14 by using rapid, one-pot
procedures under microwave enhanced conditions.
Acknowledgement
3-benzyl-quinazolin-4-one-[4-14C] 2c: 2c was prepared accord-
ing to the above-described procedure by heating a mixture of
benzyl formamide 9c (1350 mg, 10 mmol), 2-aminobenzoic
acid-[carboxyl-14C] 6a (1370 mg,905.29 MBq), and a few drops
of N,N-dimethylacetamide under microwave irradiation (6 min
at 385 W, radiochemical yield: 71%). (Rt: 2.8 min),1H-NMR
(Cl3CD, TMS): d8.34, dd, 1H; d8.12, s, 1H; d7.70–7.78, m, 2H;
d7.52–7.61, m, 1; d7.33–7.37, m, 5H; d5.21, s, 2H., MS (70 eV):
m/z = 238 (M1).
2-Amino-benzamide[carboxyl-14 C] 6b: To a stirred solution of
2-aminobenzonitrile-[cyano-14C] 5 (1111.78 MBq, 1447 mg) in
DMSO (5.25 ml) cooled in an ice bath was added H2O2 (30%,
2.1 ml) and potassium carbonate (350 mg). The mixture was then
allowed to warm up to room temperature. After one hour,
distilled water (90 ml) and ethyl acetate (100 ml) were added to
We gratefully acknowledge the help of Dr R. Dowlatabadi
(Tehran University of Medical Science, Faculty of Pharmacy)
and Mr N. Ali-Reza Zadeh (AEOI) for 1H-NMR spectroscopy
and radioactivity determination of synthesized samples,
respectively.
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