Preparation of a carbon-14 analog of 2-[2-(4-(dibenzo[b, f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy]ethanol

Article abstract of DOI:10.1134/S1066362216050131

2-[2-(4-(Dibenzo[b, f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy]ethanol (Quetiapine) labeled with ¹⁴C in 11-position was synthesized in five steps from [carboxy-¹⁴C]anthranilic acid. The key precursor of the target product is [11-

Full text of DOI:10.1134/S1066362216050131

ISSN 1066-3622, Radiochemistry, 2016, Vol. 58, No. 5, pp. 528–531. © Pleiades Publishing, Inc., 2016.
Published in Russian in Radiokhimiya, 2016, Vol. 58, No. 5, pp. 455–457.
Preparation of a Carbon-14 Analog
of 2-[2-(4-(Dibenzo[b, f][1,4]thiazepin-11-yl)piperazin-
1-yl)ethoxy]ethanol1
N. Saadatjoo*a, M. Javaheria,b, N. Saemianb, and M. Aminic
a Department of Organic Chemistry, Faculty of Chemistry, Semnan University,
P.O. Box 35131-19111, Semnan, Iran
b Applied Radiations Research School, Nuclear Science and Technology Research Institute,
P.O. Box 11365-3486, Tehran, Iran
c Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research
Center, Tehran University of Medical Sciences, Tehran, 14176 Iran
*e-mail: nsaadatjoo@semnan.ac.ir
Received January 22, 2016
Abstract—2-[2-(4-(Dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy]ethanol (Quetiapine) labeled with
14C in 11-position was synthesized in five steps from [carboxy-14C]anthranilic acid. The key precursor of the
target product is [11-14C]dibenzothiazepin-11(10H)-one. The reaction is performed as one-pot process.
Keywords: Quetiapine, labeling, antipsychotic drugs
DOI: 10.1134/S1066362216050131
Tricyclic ring systems containing a dibenzo struc-
ture joined to a central seven-membered heteroring
with a basic side chain have been a rich source of bio-
logically active molecular entities and frequently show
effects on the central nervous system [1–4]. During the
last 40 years, a number of antipsychotic agents belong-
ing to the chemical class of dibenzo epines have been
introduced (e.g., Clozapine, Loxapine, Clothiapine and
their analogs). Among this series of compounds,
Quetiapine is one of the most widely used antipsy-
chotic drugs, which acts as an antagonist for multiple
neurotransmitter receptor sites, including serotonin
(5HT1A, 5HT2A), dopamine (D1, D2), histamine (H1),
and adrenaline (Alpha1, Alpha2) in the brain, as an
antipsychotic agent, and as an antischizophrenic.
Quetiapine has a lower affinity for D2 receptors than
dopamine, leading to an alternating D2 blockade and
contributing to the impressive tolerability profile of the
substance. Quetiapine may act on depression through
its antagonism of 5-HT2A receptors and on mania
through its antagonism of D2 receptors. The compound
was also found to be useful in the treatment of acute
bipolar mania, either as a monotherapy or in combina-
tion with other mood stabilizers; it was useful as
a monotherapy in acute bipolar depression [5–8]. How-
ever, the precise mechanism of the action of this com-
pound is unknown [9]. Therefore, to further elucidate
the mechanism of action and to support ongoing me-
tabolism studies, there arose a need for analogs
of these compounds labeled with 14C in a biologically
stable site. In our previous papers [10, 11], we reported
a convenient method for 14C labeling of Clozapine
and Loxapine. Here we describe the synthesis of 2-[2-
(4-[11-14C]dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-
1-yl)ethoxy]ethanol (11-[14C]Quetiapine). The key
step of the synthesis is one-pot transformation of
[11-14C]thiazepin-11(10H)-one into the target product.
This precursor, in turn, is prepared in four steps from
[carboxy-14C]anthranilic acid.
Quetiapine (1)
1 The text was submitted by the authors in English.
528

PREPARATION OF A CARBON-14 ANALOG
529
The synthetic pathway is shown below. After con-
version of potassium [14C]cyanide to [11-14C]anthra-
nilic acid 2 [12, 13], it was converted to [carboxyl-
14C2]dithiosalicylic acid 3 via reaction with sodium
nitrite in hydrochloric acid, followed by treatment of
the resulting diazonium compound with a sodium di-
sulfide solution [14]. The coupling of 3 with 1-chloro-
2-nitrobenzene 4 was carried out in the presence of
sodium hydroxide in water, and compound 5 was pro-
duced in 81% yield [15]. In the next step, after reduc-
tion of 5 to 6 in the presence of hydrazinium monofor-
mate solution and zinc powder in methanol [16],
the key [11-14C]thiazapine-11-one was obtained in
good yield by the cyclization of 6 in the presence of
sulfuric acid in xylene for 15 h [17–19]. In the final
step, dibenzo[b,f][1,4]thiazepin-11(10H)-one 7 was
converted to [11-14C]Quetiapine 1 via a one-pot syn-
thetic procedure by using pyrophosphoryl chloride
(P2O3Cl4, a green reductive chlorination agent) in the
presence of 4-hydroxyethoxyethylpiperazine (HEEP)
and N,N-dimethylaniline (DMA) in toluene in almost
quantitative yield [20].
Quetiapine fumarate. It consisted of a 1525 Binary
HPLC pump and a 2487 Dual λ absorbance detector
set at 230 nm. Samples were injected with a Rheodyne
7725(i) (Cotati, CA, the United States) injection valve
equipped with a 20-μL sample loop. Waters Breeze
chromatographic software was used for data acquisi-
tion and processing. A Welcrom C18 column (4.6 ×
250 mm, 5 µm) was used for separation. The isocratic
mobile phase consisted of 10 mM phosphate buffer
(pH 3) and acetonitrile (50 : 50 v/v). It was fed at a
flow rate of 1.0 mL min–1 at ambient temperature
(25°C). The radioactivity was determined with a Beck-
man LS6500 liquid scintillation spectrometer. The
mass spectra were taken with a Finnigan TSQ-70 in-
strument.
[Carboxyl-14C2]dithiosalicylic acid, 3. [Carboxyl-
14C]anthranilic acid 2 with a specific activity of
200 MBq mmol–1 was prepared according to our previ-
ous report [15]. To an aqueous solution of [carboxyl-
14C]anthranilic acid (685 mg, 1000 MBq, 5 mmol) in
water (5 mL) and concentrated hydrochloric acid
(1 mL) at 5°C, a solution of sodium nitrite (345 mg) in
water (2.5 mL) was added at such a rate as to keep the
temperature below 5°C. The resulting solution of the
diazonium derivative was slowly added to the alkaline
sodium disulfide solution, keeping the temperature
below 5°C. Then, the mixture was allowed to warm up
to room temperature. After the evolution of nitrogen
ceased, a solution of concentrated hydrochloric acid
(0.9 mL) was added. Then, the resulting precipitate of
[carboxyl-14C]dithiosalicylic acid 3 was filtered off
and washed with water. After that, the precipitate was
dissolved in a solution of anhydrous sodium carbonate
(300 mg) in water (10 mL) by heating, and the mixture
was filtered while hot. Finally, the [carboxyl-14C]di-
thiosalicylic acid 3 was reprecipitated by adding con-
centrated hydrochloric acid. The resulting product was
filtered off, washed with cooled water and ether, and
dried under vacuum to give 3 (655 mg, 850 MBq,
2.14 mmol) in 86% yield. IR (KBr): 3100, 2600, 1675,
1250, 1450 cm–1.
Scheme of the synthesis of 1. (a) NaNO2, HClaq; (b) Na2S2;
(c) NaOHaq; (d) hydrazinium monoformate, Zn, MeOH;
(e) H2SO4, xylene; ( f ) P2O3Cl4, HEEP, DMA, toluene.
Preparation of Na2S2. Powdered sulfur (170 g)
was added to a solution of sodium sulfide (Na2S·
9H2O) (1.3 g) in boiling water (1.5 mL). After dissolv-
ing the sulfur powder on heating with stirring, a solu-
tion of NaOH (200 mg) in water (0.5 mL) was added,
and the resulting mixture was cooled to room tempera-
ture and finally in an ice–salt bath.
Barium [14C]carbonate was converted to potassium
[14C]cyanide using the standard procedure [14]. The IR
spectra were recorded on a Bruker FT-IR Vector 22
1
instrument, and the H NMR spectra, on a Varian
Unity Plus 400 spectrometer (400 MHz). A Waters
HPLC system (Waters, Milford, MA, the United
States) was used for chromatographic determination of
[Carboxyl-14C2]-2-(2-nitrophenylthio)benzoic acid,
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SAADATJOO et al.
7.30–7.40 (t, 1H), 7.40–7.60 (m, 4H), 7.60–7.70
5. 1-Chloro-2-nitrobenzene (675 mg) was added to a so-
lution of dithiosalicylic acid 3 (625 mg, 811.06 MBq,
2.04 mmol) and NaOH (325 mg) in water (2.5 ml), and
the mixture was refluxed at 100–105°C for 5 h. After
the extraction of the reaction mixture with ethyl acetate
(2 × 5 mL), the aqueous layer was neutralized with a
hydrochloric acid solution and then extracted with
ethyl acetate (2 × 5 mL). The organic layer was dried
over anhydrous magnesium sulfate and filtered, and
the solvent was removed under reduced pressure to
give [carboxyl-14C2]-2-(2-nitrophenylthio)benzoic acid
5 (1010 mg, 728.25 MBq, 3.67 mmol) in 89.8% yield.
IR (KBr): 3320, 1679, 1573, 1523, 1448, 1341, 1259,
(d, 1H), 10.70 (d, 1H). MS (70 eV): m/z = 230 (M + 1).
2-[2-(4-([11-14C]Dibenzo[b,f ][1,4]thiazepin-11-
yl-1-piperazinyl)ethoxy]ethanol, 1. Pyrophosphoryl
chloride (0.28 mL) was added to a solution of di-
benzo[b,f][1,4]thiazepin-11(10H)-one 7 (675 mg,
588.95 MBq, 2.97 mmol) and N,N-dimethylaniline
(400 mg) in dry toluene (4 mL). After stirring the re-
sulting suspension at 20–25°C for 30 min, the reaction
mixture was refluxed at 110–112°C for 4.5 h. After
slowly cooling the reaction mixture to 25°C, 4-hy-
droxyethoxyethylpiperazine (2.1 g, 4 equivalents) was
added to the resulting iminochloride intermediate.
After refluxing the reaction mixture at 105–107°C for
21 h, a NaOH solution (7 mL, 5%) was added to the
reaction mixture over a period of 15 min at room tem-
perature. The mixture was stirred for an additional
30 min, after which the organic and aqueous phases
were separated. The organic phase was washed with
water (15 mL), the layers were separated, and water
(5 mL) was added to the organic phase. The product
was converted to its water-soluble HCl salt by adding
concentrated HCl to pH between 2 and 3. The aqueous
phase was separated, 10 mL of dichloromethane was
added, and the mixture was alkalized to pH 10–11 with
a 25% NaOH solution (10 mL). The dichloromethane
phase was separated, dried over sodium sulfate, fil-
tered, and the dichloromethane was distilled off under
reduced pressure to obtain [11-14C]Quetiapine 1 as free
base (1.125 g, 583 MBq, 2.94 mmol) in 99% yield.
HPLC (conditions see above) Rt 2.50 min. IR (KBr):
3318, 2869, 1600, 1413 cm–1. 1H NMR (CDCl3, TMS),
δ, ppm: 2.45–2.55 (m, 2H), 2.45–2.70 (m, 2H), 3.60–
3.70 (m, 6H), 3.70–3.80 (m, 6H), 6.85 (d, 1H, J =
8.0 Hz), 7.10 (m, 1H), 7.20 (d, 1H, J = 7.6 Hz), 7.25–
7.40 (m, 4H), 7.55 (m, 1H). MS (70 eV): m/z = 386
(M + 1).
1
1146, 1102, 850, 750 cm–1. H NMR (DMSO-d6,
TMS), δ, ppm: 10.5 (br.s), 8.0 (d.d, 1H), 7.5 (t, 1H),
7.2 (m, 2H), 7.1 (d.d, 3H), 6.9 (t, 1H).
[Carboxyl-14C]-2-(2-aminophenylthio)benzoic
acid, 6. A suspension of [carboxyl-14C]-2-(2-nitro-
phenylthio)benzoic acid 5 (1000 mg, 721.04 MBq,
3.63 mmol) and zinc dust (475 mg) in methanol
(3 mL) was stirred in a nitrogen atmosphere with hy-
drazinium monoformate (1.5 mL) at room temperature.
After the reaction completion (monitored by TLC), the
reaction mixture was filtered through Celite. The fil-
tered mixture was evaporated, and the residue was dis-
solved in chloroform and washed with a concentrated
aqueous NaCl solution to remove excess hydrazinium
monoformate. The organic layer was dried over anhy-
drous magnesium sulfate and filtered, and the solvent
was removed under reduced pressure to give com-
pound 6 (820 mg, 663.45 MBq, 3.34 mmol) in 92%
yield.
Preparation of hydrazinium monoformate solu-
tion. Hydrazinium monoformate was prepared by
slowly neutralizing equimolar amounts of hydrazine
hydrate and 85% formic acid in an ice water bath with
stirring.
ACKNOWLEDGMENTS
[11-14C]-10H-Dibenzo[b,f][1,4]thiazepin-11-one,
7. A solution of [carboxyl-14C]-2-(2-aminophenylthio)-
benzoic acid 6 (800 mg, 647.25 MBq, 3.26 mmol) in
xylene (10 mL) with the addition of sulfuric acid
(0.1 mL) was refluxed at 145–150°C for 6 h. Then
the mixture was cooled to room temperature, after
which the resulting solid was filtered off and washed
with methanol. The solid was dried under reduced
pressure to give [11-14C]thiazepin-11-one 7 (675 mg,
588.95 MBq, 2.97 mmol) in 91% yield. IR (KBr):
The authors are grateful to Dr. M. Amini (Faculty
of Pharmacy, Tehran University of Medical Science)
1
for taking the H NMR spectra and to Mrs. J. Karimi
(AEOI) for measuring the radioactivity of the synthe-
sized samples. The authors gratefully acknowledge the
help of the Department of Organic Chemistry, Faculty
of Chemistry, Semnan University.
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