Syntheses of the tricyclic cores of clozapine, dibenzo[b,f][1,4]thiazepin- 11(10H)-one, and dibenzo[b,f][1,4]oxazepin-11(10H)-one in C-14 labeled form by [14C]carbonylation

Article abstract of DOI:10.1002/jlcr.1802

Clozapine has been demonstrated to bind covalently to proteins as a result of metabolic activation that has been proposed to be a precursor to the serious side effects including death that occur in a small percentage of the population. The covalent modifi

Full text of DOI:10.1002/jlcr.1802

Research Article
Received 26 March 2010,
Revised 3 May 2010,
Accepted 2 June 2010
Published online 5 August 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1802
Syntheses of the tricyclic cores of clozapine,
dibenzo[b,f][1,4]thiazepin-11(10H)-one, and
dibenzo[b,f][1,4]oxazepin-11(10H)-one in
C-14 labeled form by [14C]carbonylation
Ã
Charles S. Elmore, Peter N. Dorff, and J. Richard Heys
Clozapine has been demonstrated to bind covalently to proteins as a result of metabolic activation that has been proposed
to be a precursor to the serious side effects including death that occur in a small percentage of the population. The covalent
modification of proteins by clozapine has been studied by several groups and is well documented; therefore, the
department of drug metabolism desired to use [14C]clozapine as a positive control for covalent binding assays. The
preparation of [14C]clozapine was first conducted using a previous reported route and then using a new route that utilized
[
14C]carbonylation as the isotope incorporating step. While this route worked, it was not deemed superior to the previous
route. However, this methodology proved quite effective in preparing C-14 labeled dibenzothiazepine and dibenzoxapine
ring systems.
Keywords: [14C]carbonylation; clozapine; loxapine; amoxapine; tricyclic ring
metabolism for evaluation as a positive control in covalent
binding studies.
Introduction
Clozapine is a tricyclic antipsychotic medication that is currently
marketed for the treatment of schizophrenia.1 It has a turbulent
past that includes being withdrawn from the US market in
Results and discussion
Drug metabolism desired the C-14 label placed in the tricyclic
core of clozapine and the amidine carbon seemed the most
accessible site for radiolabeling. [14C]Clozapine labeled in this
location has been reported twice previously6 and when we
repeated the reported procedures, they worked admirably to
prepare the compound in 30% overall yield (Scheme 2).
1975 for causing the death of several patients due to
agranulocytosis.2 In 1989, the FDA re-admitted clozapine to
the US market for treatment-resistant schizophrenia and it is
now used in conjunction with careful blood monitoring.3
Agranulocytosis occurs in 0.8–1% of the patient population
and has been proposed to arise from the covalent binding
of clozapine to neutrophils or their biological precursors.4
A nitrene metabolite of clozapine or of one of clozapine’s other
metabolites is suspected to be the culprit, leading to the
covalent modification of proteins (Scheme 1).
The generation of reactive metabolites is a major concern
during the drug development process and has received
considerable attention from major pharmaceutical companies
over the past few years.5 While many marketed drugs display
high covalent binding to proteins, it is difficult if not impossible
to predict which protein modifications will lead to toxicity.
Therefore, the propensity to form reactive metabolites needs to
be minimized during the compound design phase to avoid the
formation of potential reactive metabolites that could lead to
toxicological findings.
In an effort to improve upon this route, we envisioned the key
intermediate [14C]-1 as arising from a [14C]carbonylation of an
aryl bromide instead.7 This would shorten the radiochemical
steps from five to two and might improve upon the radio-
chemical yield of 30% (47% to [14C]-1) that was achieved when
we reproduced the literature route. Therefore, bromide 3 was
prepared in two steps by nucleophilic aromatic substitution to
afford nitroarene 2 and subsequent reduction of the nitro group
to afford aniline 3 in high yield (Scheme 3). Bromide 3 was then
subjected to [14C]carbonylation using standard methodology in
the presence of triethylamine, but only a low yield of [14C]-1 was
observed. When the base was changed from triethylamine to
sodium acetate, an 83% crude yield (42% radiochemical yield) of
[
14C]-1 was obtained, but after preparative HPLC only a 52%
Many companies have implemented an assay to determine
the levels of covalent binding to a biological matrix such as liver
microsomes or hepatocytes. To insure the proper performance
of the assay and the quality of the hepatocytes used in the
assay, a substrate must be used as a positive control. Therefore,
[14C]clozapine was requested by the department of drug
Isotope Chemistry, CNS Chemistry, AstraZeneca Pharmaceuticals LP, 1800
Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA
*Correspondence to: Charles S. Elmore, 911 Barley Ct., Landenberg, PA 19350, USA.
E-mail: chad_elmore@yahoo.com
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Copyright r 2010 John Wiley & Sons, Ltd.

C. S. Elmore et al.
R
R
N
N
N
N
toxicity
(agranulocytosis)
N
N
N
N
Cl
Cl
H
R=CH3
R=H
clozapine
Putative Reactive Metabolite
desmethylclozapine
R=CH3, O clozapine N-oxide
Scheme 1. Proposed metabolic process leading to toxicity of clozapine.
14CN
Cl
Cl
NO2
14CN
I
NH2
Cu14CN,
K2CO3, H2O2,
DMSO
NH
NO2
NH2
DMF, 130 °C
Cs2CO3, DMSO
84%
98%
63%
Cl
N
O
14C
O
N
NH2
14C
HN
N
14C
HN
SnCl2, HOAc,
NH
N
TiCl4, PhCH3,
NO2
EtOH, 85 °C
N
Cl
N
H
Cl
100°C,
H
88%
66%
[
14C]-1
[11-14C]clozapine
Cl
Scheme 2. Preparation of [14C]clozapine according to the previously reported route in 30% radiochemical yield over steps steps.
Cl
NO2
NH
Cl
F
NH2
Fe, NH4Cl,
Br
K2CO3
acetone
78%
Br
EtOH, THF, H2O
95%
NO2
2
Cl
NH2
NH
O
HN
14C
Pd(PPh3)4, 14CO
NaOAc, DMF
Cl
Br
N
H
[
14C]-1
52%
3
(26% radiochemical)
Scheme 3. Preparation of diazepine [14C]-1 via [14C]carbonylation.
yield (26% radiochemical) of the target was obtained. This yield sample. Thus, despite being only one radiochemical step, this
is about half that of the previously reported route owing route suffers from the need to use an excess of the C-14 reagent
partially to the necessity of performing preparative HPLC to and thus from a significantly lower radiochemical yield than that
remove some close eluting non-radioactive impurities from the reported by Matloubi and co-workers. However, it does allow for
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J. Label Compd. Radiopharm 2010, 53 787–792

C. S. Elmore et al.
the utilization of non-radioisotope using groups to prepare the give aniline [14C]-10 and the aniline was cyclized using
[14C]carbonylation precursor and for the long-term storage of trimethylaluminum to afford the thiazepine [14C]-7 in 15%
the non-radioactive intermediate 3.
We then extended our investigation to other tricyclic ring
overall yield from Ba14CO3.
The [14C]carbonylation substrate was prepared in a manner
systems; first turning our attention to the synthesis of oxepine analogous to that previously described for 3 to give bromide
14C]-4, which is the tricyclic core of [14C]loxapine and precursor 12 (Scheme 6). The [14C]carbonylation was initially
[
[14C]amoxapine. The bromo precursor for the [14C]carbonylation performed with triethylamine, and this reaction afforded a 20%
was synthesized in a manner analogous to that described for 3 isolated yield of [14C]-7. Switching to sodium acetate dramati-
in moderate yield, and the [14C]carbonylation afforded a 57% cally improved the yield to give 50% isolated yield (32%
crude yield of the target compound (Scheme 4). After radiochemical yield). This improvement in yield with the use of
preparative HPLC, a 36% yield (26% radiochemical yield) of NaOAc was also observed in the synthesis of [14C]-1.
oxepine [14C]-4 was obtained. Despite the low yield this does
provide a rapid synthesis of the oxepine core.
Finally, we turned our attention to the thiazepine ring system.
Experimental
We had previously prepared [14C]-7 using a route similar to that
General
published for [14C]clozapine (Scheme 5). Carboxylation of the
dianion formed from thiophenol afforded the thiol [14C]-8 in low Pd(PPh3)4 was obtained from Strem Chemical Company and
yield. The low yield may have been due to the formation of Na14CO2H (57 mCi/mmol) and Ba14CO3 (57 mCi/mmol) were
phenylthioester or disulfide of [14C]-8 with the excess thiophe- obtained from American Radiolabeled Chemicals, Inc. All other
nol in the reaction mixture. Attempts at converting the thioester reagents were obtained from Acros and Aldrich and were used
to [14C]-8 were unsuccessful. Thiol [14C]-8 was then coupled without purification. 1H NMR and 13C NMR spectra were
with 2-chloronitrobenzene to give the acid that was esterified to recorded on Bruker Avance 500 and Avance 600 with Dual
give [14C]-9. Nitroarene [14C]-9 was reduced with zinc metal to Cryoprobe spectrometers in CDCl3 and were referenced to the
NO2
O
OH
Br
Fe, NH4Cl,
EtOH, THF, H2O
83%
Cs2CO3
DMF, 60 °C
60%
NO2
Br
F
Cl
Cl
R
N
5
NH2
O
N
O
N 14C
HN
14C
Pd(PPh3)4, 14CO
NaOAc, DMF
36%
Cl
Cl
Br
O
O
[
14C]-4
R=CH3
R=H
[
[
14C]loxapine
14C]amoxapine
(26% radiochemical)
Cl
6
Scheme 4. Preparation of oxepine [14C]-4 as an intermediate toward [14C]lox pine or [14C]amoxapine.
NO2
1.
14CO2H
NO2
14CO2Me
Cl
14CO2, BuLi,
TMEDA, cyHex
30%
SH
HS
S
NaH, Me2NAc
2. MeI
14C]-8
87%
[
14C]-9
[
O
HN 14C
S
14C]-7
NH2
14CO2Me
Me3Al,
Zn, NH4Cl,
MeOH,
73%
S
CH2Cl2
79%
[
14C]-10
[
Scheme 5. Preparation of thiazepine [14C]-7 by carboxylation.
J. Label Compd. Radiopharm 2010, 53 787–792
Copyright r 2010 John Wiley & Sons, Ltd.
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C. S. Elmore et al.
NO2
S
SH
Fe, NH4Cl,
EtOH, THF, H2O
95%
K2CO3
acetone
78%
Br
NO2
Br
F
11
NH2
S
O
HN
14C
Pd(PPh3)4, 14CO
NaOAc, DMF
50%
Br
S
[
14C]-7
(32% radiochemical)
12
Scheme 6. Preparation of thiazepine [14C]-7 by [14C]carbonylation.
residual solvent peak (7.26 and 77.00 ppm). LC/MS analyses were (1.16 g, 20.7 mmol) was added. The resulting slurry was warmed
performed on an HP MSD-1100 using a Luna-C18(2) column, to 851C and was stirred overnight. After cooling to room
with a 10–100% gradient of MeOH-0.1% aqueous formic acid temperature, the slurry was filtered through celite and the
over 10 min and electrospray ionization. HPLC analyses were filtrate was diluted with 100 mL of water, 100 mL of CH2Cl2 and
performed using a Agilent 1100 series HPLC system using either 50 mL of saturated NaHCO3. The layers were separated and the
method A (10/90 to 100/0 MeOH/0.1% aqueous TFA gradient aqueous layer was extracted three times with 50 mL of CH2Cl2.
elution over 20 min, Phenomenex Polar-RP), method B (10/90 to The combined organic layers were dried (MgSO4) and filtered
100/0 MeCN/0.1% aqueous TFA gradient elution over 10 min, and the resulting solution was concentrated to give 177 mg of a
Phenomenex Luna C-18(2)), or method C (50/50 to 100/0 MeOH/ brown oil. Purification by silica gel chromatography (10–60%
0.1% TFA over 20 min, Phenomenex Polar-RP). All HPLC analyses over 20 min) afforded 105 mg of an off white solid (67%). 1H
were conducted using a flow rate of 1 mL/min on 4.6 Â 100 mm NMR dppm 6.54 (dd, J = 8.1, 1.1 Hz, 1H), 6.69 (td, J = 7.3, 1.5 Hz,
columns heated to 301C and concluded with a 5 min wash of 1H), 6.73 (dd, J = 8.4, 2.3 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 7.03 (d,
100% MeOH or MeCN. Preparative HPLC was conducted on a J = 8.2 Hz, 1H), 7.11 (td, J = 7.5, 1.2 Hz, 1H), 7.50 (dd, J = 7.9, 1.2 Hz,
21.2 Â 250 mm 5 m Thermo Scientific Hypersil Gold C18 column 1H). 13C NMR dppm 110.4, 114.2, 115.6, 118.8, 119.9, 125.1,
using MeOH-0.1% aqueous TFA with a flow rate of 15 mL/min 128.3, 128.4, 132.3, 132.7, 142.8, 144.4. GC/MS: 298 (100%), 296
and a gradient elution of 50 to 100% over 40 min. GC/MS (81%), 300 (26%).
analyses were conducted with a Hewlett Packard 6890 GC
system and 5973 Mass Selective Detector using a temperature
[11-14C]8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one ([14C]-1)
gradient of 70–2601C over 20 min.
A three-necked, round-bottom flask containing sodium [14C]
formate (5.6 mg, 4.5 mCi, 0.08 mmol) was fitted with a septum,
N-(2-Bromophenyl)-4-chloro-2-nitroaniline (2)
a vacuum outlet and a 901 bent adapter to which was attached
a round-bottom flask containing a solution of bromide 3 (11 mg,
0.04 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol), and NaOAc (95 mg,
1.16 mmol) in 7 mL of DMF. The apparatus was evacuated to
approx. 1 mm Hg and the valve leading the vacuum was closed.
Sulfuric acid (24 mL) was added through the septum to the
sodium [14C]formate, and the resulting solution was stirred for
1 h at 1201C. The DMF solution was warmed to 1001C and was
stirred overnight. The sample was removed from the apparatus
to give 4 mCi (43% radiochemical purity) and was purified
by preparative HPLC to give 1.2 mCi (52%, 26% radiochemical)
at a radiochemical purity of 98% (method C). 1H NMR ppm 6.97
(d, J = 8.5 Hz, 1H), 7.07 (dd, J = 8.5, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz,
1H), 7.44 (m, 2H), 7.50 (m, 1H), 7.55 (m, 1H), 7.72 (br. s, 1H), 8.70
(br. s., 1H). LC/MS (M1H): 247 (100%), 249 (32.1%), 248 (13.7%),
244 (8.1%).
A slurry of 2-bromoaniline (0.670g, 3.89mmol), 4-chloro-1-fluoro-
2-nitrobenzene (0.394g, 2.24mmol), and Cs2CO3 (0.756g,
2.32mmol) in 6 mL of DMF was stirred overnight under N2 at
1001C. The solvent was removed and the residue partitioned
between 10mL of water and 10mL of CH2Cl2. The layers were
separated and the aqueous layer extracted twice with 10mL
CH2Cl2. The combined organic layers were dried (MgSO4) and
filtered, and the filtrate was concentrated to dryness to give
523 mg of a brown oil. The oil was purified by silica gel
chromatography (0–100% Hex-EtOAc over 25min) and the
product containing fractions were combined and concentrated
1
to dryness to afford 294 mg (40%) of a red solid. H NMR dppm
7.05 (d, J = 9.2 Hz, 1H), 7.12 (td, J = 7.5, 1.5 Hz, 1H), 7.34 (dd, J = 9.0,
2.6 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.40 (dd, J = 7.9, 1.5 Hz, 1H), 7.70
(d, J = 7.3 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 9.38 (br. s., 1H). 13C NMR
dppm 117.6, 119.8, 123.1, 125.2, 126.0, 127.1, 128.4, 134.0, 135.7,
137.2, 140.5 (HMBC shows that the peak at 134.0 has two
overlapping carbons). GC/MS: 328 (100%), 326 (80%), 324 (26%).
2-Bromo-4-chloro-1-(2-nitrophenoxy)benzene (5)
A slurry of 2-bromo-4-chlorophenol (1.48 g, 7.12 mmol) and
Cs2CO3 (3.91 g, 12.00 mmol) in 20 mL of DMF was treated with
1-fluoro-2-nitrobenzene (956 mg, 6.78 mmol) as described for 2
to afford 1.334 g (60%) of a solid. 1H NMR dppm 6.88 (dd, J = 8.2,
1.1 Hz, 1H) 6.95 (d, J = 8.7 Hz, 1H) 7.24 (td, J = 7.8, 1.2 Hz, 1H) 7.29
(dd, J = 8.7, 2.4 Hz, 1H) 7.52 (ddd, J = 8.2, 7.0, 1.6 Hz, 1H) 7.66
N1-(2-Bromophenyl)-4-chlorobenzene-1,2-diamine (3)
A solution of nitroaniline 2 (172 mg, 0.53 mmol) in 10 mL of
ethanol, 6 mL of THF, 2 mL of water, and 1 mL of saturated
aqueous NH4Cl was stirred vigorously under N2 as iron powder
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C. S. Elmore et al.
(d, J = 2.4 Hz, 1H) 7.99 (dt, J = 8.2, 0.9 Hz, 1H). 13C NMR dppm to 751C and stirred overnight. After cooling to room tempera-
115.7, 119.4, 121.6, 123.8, 126.1, 129.1, 130.9, 133.7, 134.4, 140.8, ture, MeI (173 mg, 1.22 mmol) was added and the solution was
149.8, 151.2. GC/MS: 329 (100%), 327 (78%), 331 (25%).
stirred for 3 h. It was then poured into 100 mL of water and was
extracted twice with 50 mL of EtOAc. The combined organic
layers were washed with 50 mL of saturated aqueous NaCl and
were then dried (MgSO4). The solution was concentrated to
dryness to give 177 mg (34 mCi, 85% radiochemical purity
(method B), 92% yield) of a yellow solid.
2-(2-Bromo-4-chlorophenoxy)aniline (6)
A slurry of nitroarene 5 (603 mg, 1.84 mmol) and iron powder
(2.31 g, 41.3 mmol) in 8 mL of EtOH, 8 mL of THF, and 2 mL of
a solution of saturated aqueous NH4Cl, and was reacted as
described for 3 to give 457 mg (83%) of a clear oil, which
Methyl 2-(2-aminophenylthio)[14C]benzoate ([14C]-10)
1
solidified upon standing. H NMR dppm 3.80 (m, 2H), 6.71 (td,
A solution of ester [14C]-9 (33 mCi, 0.48 mmol, 85% radio-
chemical purity) and NH4Cl (65 mg, 1.2 mmol) in 3.6 mL of MeOH
was stirred as zinc powder (799 mg, 12.2 mmol) was added and
the reaction mixture was then warmed to reflux for 4 h. The
slurry was diluted with hot methanol and was filtered while still
warm through a pad of celite to give a yellow solution. The
MeOH was removed, and the solution was partitioned between
10% aqueous acetic acid and EtOAc. The layers were separated
and the aqueous layer extracted four times with 50 mL EtOAc.
The combined organic layers were dried (MgSO4) and filtered to
give 25 mCi with a radiochemical purity of 82% (method B, 73%
yield). LC/MS (M1H) 262 (100%), 263 (15.5%), 260 (8.4%).
J = 7.6, 1.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.4, 1.8 Hz,
1H), 6.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.00 (td, J = 7.7, 1.5 Hz, 1H), 7.16
(dd, J = 8.8, 2.7 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H). 13C NMR dppm
113.7, 116.7, 118.5, 118.8, 119.7, 125.6, 128.5, 128.6, 133.1, 138.4,
142.6, 152.9. GC/MS: 299 (100%), 297 (80%), 301 (26%).
[11-14C]Dibenzo[b,f][1,4]oxazepin-11(10H)-one ([14C]-4)
Sodium [14C]formate (10.3 mg, 0.15 mmol, 8.4 mCi), bromide 6
(32 mg, 0.11 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol), NaOAc
(134 mg, 1.63 mmol) and 5 mL of DMF were reacted as described
for [14C]-1 to give 4.5 mCi (65% radiochemical purity, method C).
Purification by preparative HPLC afforded 2.2 mCi (36% yield,
26% radiochemical yield) with a radiochemical purity of 99.6%
[11-14C]Dibenzo[b,f][14]thiazepin-11(10H)-one ([14C]-7)
1
(method C). H NMR dppm 7.02 (m, 1H) 7.15 (ddd, J = 7.3, 5.2,
A solution of aniline [14C]-10 (25 mCi, 82% radiochemical purity,
0.36 mmol) in 12 mL of CH2Cl2 was cooled to 01C and stirred
under Ar as 225 mL of a 2 M (0.45 mM) solution of trimethyla-
luminum in hexanes was added. The solution was stirred for
30 min at 01C and then at room temperature overnight. It was
then cooled to 01C and 2.1 mL of 1 M aqueous HCl was added
and after 10 min, 20 mL of water. The solution was then
extracted three times with 50 mL of CH2Cl2 and the combined
organic layers were washed with 50 mL of saturated aqueous
NaCl. The solution was dried (MgSO4) and then filtered to give
25 mCi at a radiochemical purity of 65% (method B, 79% yield).
LC/MS: 252 (100), 253 (15%), 250 (9%).
1.8 Hz, 2H), 7.19 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H) 7.46 (dd,
J = 8.5, 2.7 Hz, 1H) 7.91 (d, J = 2.4 Hz, 1H). 13C NMR dppm 121.3,
121.8, 122.4, 126.16, 126.21, 126.23, 130.00, 130.04, 130.8, 131.7,
134.3, 150.7, 158.1. LC/MS: 248 (100%), 250 (31%), 249 (14%),
246 (8.3%).
2-Mercapto[14C]benzoic acid ([14C]-8)
A solution of TMEDA (697 mg, 6 mmol) in 6 mL of cyclohexane
was stirred at 01C as 3.8 mL of 1.6 M (6 mmol) n-BuLi in hexane
was added followed by dropwise addition of thiophenol
(330 mg, 3.0 mmol) in 1.25 mL of cyclohexane. After complete
addition, the solution was warmed to room temperature and
stirred for 24 h. The solution was then cooled in liquid nitrogen
and was evacuated. 14CO2 (97 mCi, 1.7 mmol, generated from
336 mg (1.7 mmol) of Ba14CO3) was transferred into the reaction
flask. The reaction was warmed to room temperature and was
stirred for 16 h. The solution was then diluted with 10 mL of 2 M
HCl and was extracted five times with 25 mL of Et2O to give
75 mCi in the combined organic extracts (45% radiochemical
purity, method B). The organic extracts were extracted ten times
with 5 mL of 5% NaHCO3 and the combined aqueous layers
were extracted with Et2O after acidification with HCl. The
combined organic layer was washed with an aqueous solution
of saturated NaCl and was then dried (MgSO4). Filtration gave a
Et2O solution that contained 33.9 mCi of [14C]-8 at a radio-
chemical purity of 87% (method B, 30% yield corrected for
purity). LC/MS (M-H): 155 (100%), 153 (7.2%), 156 (6.8%).
2-Bromophenyl)(2-nitrophenyl)sulfane (11)
2-Bromobenzenethiol (0.919 g, 4.86 mmol), 1-fluoro-2-nitroben-
zene (0.915 g, 6.48 mmol), and potassium carbonate (987 mg,
7.14 mmol) in 50 mL of acetone was reacted as described for
1
compound 2 to give 1.41 g of a yellow solid. H NMR indicated
a purity of 84% with the remaining 16% being residual
2-fluoronitrobenzene (78% yield corrected for purity). 1H NMR
dppm 6.77 (d, J = 8.2 Hz, 1H) 7.25 (tt, J = 7.7, 1.1 Hz, 1H) 7.35
(m, 1H) 7.37 (m, 1H) 7.42 (tt, J = 7.5, 1.1 Hz 1H) 7.72 (dd, J = 7.6,
1.5 Hz, 1H) 7.77 (dd, J = 7.9, 1.2 Hz, 1H) 8.25 (dd, J = 8.2, 1.2 Hz,
1H). 13C NMR dppm 125.4, 125.9, 128.1, 128.8, 131.1, 131.7,
132.5, 133.6, 134.3, 137.3, 138.0, 145.3. GC/MS: 311 (100%), 309
(98%), 312 (15%).
(2-Bromophenyl)(2-aminophenyl)sulfane (12)
Methyl 2-(2-nitrophenylthio)[14C]benzoate ([14C]-9)
A slurry of nitroarene 11 (609 mg, 1.96 mmol), 12 mL of EtOH,
A solution [14C]-8 (34 mCi, 87% radiochemical purity, 0.52 mmol) 12 mL of THF, 4 mL of water, 4 mL of saturated aqueous NH4Cl
in 1.5 mL of dimethylacetamide was added to a slurry of 60% and iron powder (2.45 g, 44.7 mmol) were reacted as described
NaH dispersion in oil (48 mg, 1.2 mmol) and the resulting slurry for 3 to give 701 mg (2.5 mmol, 95% yield) of a white solid.
1
¨
H NMR appm 6.62 (d, J = 7.9 Hz, 1H) 6.78 (td, J = 7.5, 1.1 Hz, 1H)
was stirred for 30 min under Ar at room temperature. A solution
of 2-chloronitrobenzene (116 mg, 0.74 mmol) in 1 mL of 6.81 (d, J = 8.5 Hz, 1H) 6.96 (t, J = 7.6 Hz, 1H) 7.09 (t, J = 7.6 Hz, 1H)
dimethylacetamide was added and the solution was warmed 7.27(m, 1H) 7.45 (d, J = 7.9 Hz, 1H) 7.51 (d, J = 7.9 Hz, 1H). 13 C
J. Label Compd. Radiopharm 2010, 53 787–792
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C. S. Elmore et al.
NMR dppm 113.2, 115.7, 119.0, 120.8, 126.2, 126.4, 127.8, This method reduces the number of radiochemical steps and
131.8, 132.8, 137.9, 138.0, 149.2. GC/MS: 281 (100), 279 (99%), the amount of radiochemical waste generated during the
282 (15%).
synthesis.
[11-14C]Dibenzo[b,f][14]thiazepin-11(10H)-one ([14C]-7)
Sodium [14C]formate (11 mg, 0.16 mmol, 8.8 mCi, 56 mCi/mmol),
bromide 12 (28 mg, 0.10 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol),
NaOAc (88 mg, 1.1 mmol) and 3 mL of DMF were reacted
according to the procedure reported for [14C]-1 to give
4.0 mCi (90% radiochemical purity by HPLC, method C).
Purification by preparative HPLC afforded 2.8 mCi (0.05 mmol,
56 mCi/mmol, 50% yield, 32% radiochemical yield) at a radio-
chemical purity of 97% (method C). 1H NMR dppm 7.10 (dd,
J = 7.9, 1.1 Hz, 1H) 7.14 (td, J = 7.6, 1.3 Hz, 1H) 7.30 (td, J = 7.8,
1.4 Hz, 1H) 7.37 (td, J = 7.5, 1.5 Hz, 1H) 7.40 (td, J = 7.3, 1.7 Hz, 1H)
7.51 (dd, J = 7.6, 1.4 Hz, 1H) 7.57 (dd, J = 7.7, 1.3 Hz, 1H) 7.84 (dd,
J = 7.6, 1.8 Hz, 1H). LC/MS: 252 (100), 253 (15%), 250 (9%).
References
[1] O. Agid, S. Kapur, G. Remington, Expert Opin. Emerging Drugs
2008, 13, 479–495.
¨
¨ ¨
¨
[2] J. Idanpaan-Heikkila, E. Alhava, M. Olkinuora, I. Palva, Lancet 1975,
306, 611.
[3] (a) H. Y. Meltzer, Curr. Med. Res. Opin. 1997, 14, 1–20;
(b) M. Naheed, B. Green, Curr. Med. Res. Opin. 2001, 17,
223–229.
[4] (a) I. Gardner, J. S. Leeder, T. Chin, N. Zahid, J. P. Uetrecht,
Mol. Pharmacol. 1998, 53, 999–1008; (b) D. P. Williams,
M. Pirmohamed, D. J. Naisbitt, J. L. Maggs, B. K. Park,
J. Pharmacol. Exp. Ther. 1997, 283, 1375–1382; (c) F. H. J. Claas,
Psychopharm. 1989, 99, S113–S117.
[5] (a) D. C. Evans, A. P. Watts, D. A. Nicoll-Griffith, T. A. Baillie,
Chem. Res. Toxicol. 2004, 17, 3–16; (b) R. S. Obach, A. S. Kalgutkar,
J. R. Soglia, S. X. Zhao, Chem. Res. Toxicol. 2008, 21,
1814–1822.
[6] (a) U. B. Sunay, K. C. Talbot, V. Galullo, J. Label. Compd.
Radiopharm. 1992, 31, 1041–1047; (b) H. Matloubi, M. Ghandi,
M.-R. Zarrindast, N. Saemian, App. Rad. Isotopes 2001, 55,
789–791.
Conclusion
We have demonstrated that [14C]carbonylation can be an
effective means of incorporating C-14 into tricyclic ring systems,
which are present in a significant number of antipsychotics.
Although the yields are modest and the purification can be
difficult, the routes given here provide rapid access to the C-14
labeled thiazepine, diazepine and oxepine ring systems.
[7] C. S. Elmore, D. C. Dean, D. G. Melillo, J. Label. Compd.
Radiopharm. 2000, 43, 1135–1144.
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