Synthesis of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)[carbonyl- 11C]acetamide ([carbonyl- 11C]DAA1106) and analogues using [11C]carbon monoxide and palladium(0) complex

Article abstract of DOI:10.1002/jlcr.1437

N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetomide (DAA1106), a potent and selective ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with ¹¹C at the carbonyl position using a low

Full text of DOI:10.1002/jlcr.1437

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 1192–1199.
Published online 10 September 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1437
JLCR
Research Article
Synthesis of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-
phenoxyphenyl)[carbonyl-11C]acetamide
([carbonyl-11C]DAA1106) and analogues using [11C]carbon
monoxide and palladium(0) complex
1
1,2,
˚
¨
OBAIDUR RAHMAN and BENGT LANGSTROM
*
1 Department of Biochemistry and Organic Chemistry, Box 576, Husargatan 3, BMC, S-751 23 Uppsala, Sweden
2 Uppsala Imanet AB, Box 967, S-751 09 Uppsala, Sweden
Received 7 May 2007; Revised 14 June 2007; Accepted 5 July 2007
Abstract: N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106),
a potent and selective
ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with 11C at
the carbonyl position using a low concentration of [11C]carbon monoxide and the micro-autoclave technique. A
combinatorial approach was applied to synthesize the analogues using similar reaction conditions. Palladium-
mediated carbonylation using tetrakis(triphenylphosphine)palladium, various amines and methyl iodide or
iodobenzene was employed in the synthesis. The 11C-labelled products were obtained with 10–55% decay-corrected
radiochemical yields and the final product was more than 97% pure in all cases. Specific radioactivity was
determined for the compound [carbonyl-11C]DAA1106 using a single experiment and a 10-mA h bombardment. The
specific radioactivity, measured 36 min after end of bombardment, was 455 GBq/mmol. Synthetic routes to the
precursors and reference compounds were also developed. The presented approach is a novel method for the
synthesis of [carbonyl-11C]DAA1106 and its analogues, and allows the formation of a library of 11C-labelled
DAA1106 analogues which can be used to optimize the performance as a potential positron emission tomography
tracer. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: [11C]carbon monoxide; [11C]DAA1106; palladium(0); micro-autoclave
Introduction
properties. The demand for new methods of synthesiz-
ing labelled molecules is increasing in medical and
biomedical research, as well as in various clinical
applications. Although the most commonly used meth-
ods for the synthesis of 11C-labelled compounds are S-,
O- and N-methylations using [11C]methyl iodide or
Positron emission tomography (PET) is a non-invasive
imaging technique that may play an important role
in the discovery of new drugs. The micro-dosing
concept of PET can be a useful strategy for speeding
up tracer development as well as being a tool in drug
development.1
[
11C]methyl triflate,2 carbonylation using [11C]carbon
monoxide at low concentration has become of interest.
Palladium-mediated carbonylation using [11C]carbon
monoxide, organohalides or triflates and different
nucleophiles has been employed in the synthesis of
11C-labelled carbonyl compounds such as ketones,3–5
amides,6–8 imides,9 hydrazides,10 etc. Photo-in-
itiated11–13 and rhodium-mediated14,15 reactions have
also been explored for carbonylation reactions using
Investigations using PET require compounds labelled
with short-lived, positron-emitting radionuclides. 11C
is very important from the synthetic point of view
because a wide range of compounds can be labelled
with this isotope without changing their biological
˚
¨
*Correspondence to: Bengt Langstrom, Department of Biochemistry
and Organic Chemistry, Box 576, Husargatan 3, BMC, S-751 23
Uppsala, Sweden. E-mail: bengt.langstrom@biorg.uu.se, bengt.
langstrom@ge.com
Contract/grant sponsor: Uppsala Imanet
Contract/grant sponsor: GE Healthcare
low concentrations of
[
11C]carbon monoxide. The
synthesis of 11C-labelled amines based on [11C]carbon
monoxide, i.e. carbonylation followed by reductive
amination, has recently been published.16
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF N-(2,5-DIMETHOXYBENZYL)-N-(5-FLUORO-2-PHENOXYPHENYL) 1193
The compound DAA1106 has been shown to be a
carbonylation strategy for 11C-labelling of DAA1106,
and the preparation of a library of its analogues with
the intention of exploring more details in the search for
improved PET tracers to study the function of PBR in
various diseases.
potent and selective ligand for peripheral benzodiaze-
pine receptor (PBR).17 PBR is an 18-kDa protein found
in the outer mitochondrial membrane of almost all
tissues, and is abundant in steroid-producing
cells.18,19 This receptor is also found on glial cells of
central and peripheral nervous systems, and its density
increases with the inflammatory reaction of the ner-
vous tissue.20 Although the exact function of PBR is not
yet established, a number of functions such as regula-
tion of steroid production, regulation of mitochondrial
membrane potential, modulation of voltage-dependent
calcium channels, cancer cell proliferation and micro-
glial activation related to brain damage have been
suggested.21 The selective PBR ligands can therefore be
potential candidates for diagnosis and treatment of
various neurodegenerative and cardiovascular dis-
eases, and a considerable effort has been invested to
develop novel ligands for PBR. A number of PBR ligands
such as PK11195, Ro5-4864, FGIN-1-27, SSR180575,
DAA1106, DAA1097, etc. (Figure 1) have been devel-
oped, and three of them (Ro5-4864,22 PK1119523 and
DAA110624) have been labelled with 11C and applied in
PET studies. Methylation using [11C]methyl iodide was
employed in the 11C-labelling of those compounds.
Moreover, we have developed a carbonylation method
for 11C-labelling of PK11195, and that method provided
the opportunity to synthesize a number of 11C-labelled
analogues of this compound.25 This paper describes a
Results and discussion
Palladium-mediated carbonylation using tetrakis(tri-
phenylphosphine)palladium(0), various amines, low
concentrations of [11C]carbon monoxide and methyl
or phenyl iodide was employed to synthesize 11C-
labelled DAA1106 and analogues (Scheme 1). By using
this method, DAA1106 and eight structurally related
analogues (*2a–*2i in Figure 2) were labelled with 11C.
The reaction was performed in a 200-mL micro-auto-
clave. The conversion of [11C]carbon monoxide to crude
products (i.e. the trapping efficiency) was >95% in all
cases, and the decay-corrected radiochemical yields of
liquid chromatography (LC)-purified products, calcu-
lated from [11C]carbon monoxide, were 10–55% (Table
1). The radiochemical purity was over 97% for all
compounds. The specific radioactivity of compound *2a
was 455 GBq/mmol when measured 36 min after the
end of a 10 mA h bombardment.
In initial experiments, the reaction was performed
with non-activated amines, i.e. amines without any
additional base, and the reaction worked poorly. The
radiochemical yield was only 5%. Amine activation has
O
O
O
N
O
F
N
O
N
N
Cl
O
N
Cl
Cl
Cl
DAA1106
PK11195
Ro-5-4864
O
N
N
O
N
Cl
O
O
N
Cl
O
N
N
F
N
H
O
SSR180575
FGIN-1-27
DAA1097
Figure 1 Some selective PBR ligands.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

¨
˚
1194 O. RAHMAN AND B. LANGSTROM
R2
R1
R2
R1
O
R
*
H
X
N
O
X
N
R3
1. BuLi
R3
2. RI, Pd(0), *CO
O
1
*2
Scheme 1
OMe
OMe
O
Ph
O
O
*
N
*
N
F
*
N
F
F
OMe
Cl
O
O
OMe
O
*2c
*2b
*2a
OMe
OMe
OMe
O
O
*
N
O
*
*
N
N
OMe
Cl
O
O
O
*2f
*2e
* 2d
OMe
OMe
O
O
O
*
*
Cl
N
O
*
N
Cl
N
OMe
OMe
OMe
OMe
O
O
*2i
*2g
Figure 2 Target 11C-labelled molecules, ꢁ ¼11C-labelled.
*2h
previously been used to improve the radiochemical
yields of 11C-labelled amides from carbonylation reac-
tions using [11C]carbon monoxide.26 Therefore, the
effect of bases such as pyridine, triethylamine, potas-
sium tert-butoxide and n-butyllithium (nBuLi) was
explored, and nBuLi was found to best improve the
radiochemical yields.
The precursors for the DAA1106 analogues were
prepared by N-alkylation of three different 2-phenoxy
anilines (3) with benzyl halides (4). The reaction was
performed in the presence of CsOH ꢀ H2O and molecular
sieves (MS) in dry N,N-dimethylformamide (DMF)
(Scheme 2).27 The yields for the precursors varied from
40 to 90% (Table 2). In cases of compounds 1e and 1h,
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

SYNTHESIS OF N-(2,5-DIMETHOXYBENZYL)-N-(5-FLUORO-2-PHENOXYPHENYL) 1195
the yields were a little lower at 45 and 40%, respec-
(1a)28 of the eight prepared amines (1a–1i) had been
described previously.
tively. In these cases, benzyl chlorides were used as
substrates, rather than benzyl bromides. Only one
The compound 5-fluoro-2-phenoxyaniline (3) used in
the N-alkylation reaction was prepared by the reduc-
tion of 4-fluoro-2-nitro-1-phenoxybenzene. The reduc-
tion was carried out using hydrazine hydrate in the
presence of ferric chloride and activated carbon,29
giving a yield of 96%. 4-Fluoro-2-nitro-1-phenoxyben-
zene was prepared as described previously.28 The two
benzyl bromides (4a and 4f) used in the N-alkylation
reactions were prepared from the corresponding benzyl
alcohols by treating with carbon tetrabromide and
triphenyl phosphine in dry dichloromethane.30 The
reaction was carried out at ambient temperature for
30 min, and the yield was over 80%. All other benzyl
halides used were commercially available. Two refer-
ence compounds (2a and 2i) of the labelled target
molecules *2a and *2i were prepared by treating the
corresponding amines with acetyl chloride in the
presence of pyridine.31 The yield was over 90% in both
cases. The reference compounds for other labelled
molecules (*2b–*2h) were not synthesized, instead
those compounds were characterized by liquid chro-
matography–mass spectrometry (LC–MS). The specific
radioactivity was determined only for compound *2a.
Table 1 Trapping efficiencies and radiochemical yields for
the 11C-labelled DAA1106 and its analogues shown in Figure 2
Product
TEa (%)
RCYb (% (n)c)
m/z (M þ 1)/g/mold)
*2a
*2b
*2c
*2d
*2e
*2f
*2g
*2h
*2i
95
95
96
98
95
95
96
95
94
40 (30)
41
70 (55)
28 (20)
40
15 (10)
41 (30)
40 (29)
47 (38)
396.15
370.09
458.26
378.16
378.16
384.09
378.16
412.12
412.12
*on the numbers in column 1 indicates 11C-labelled molecules.
a TE ¼trapping efficiency, decay-corrected; the fraction of
radioactivity left in the crude product after a nitrogen purge.
b RCY ¼radiochemical yield; decay-corrected and determined
by analytical LC based on radioactivity in the crude product
before nitrogen purging and on the purity of crude product.
The value is the mean from at least three experiments.
c Values in parenthesis are the isolated yields.
d Determined by LC–MS[ESIþ].
R3
H
X
NH2
O
R3
X
N
R2
Y
CsOH.H2O, MS
DMF
+
R1
O
R1
R2
4
3
1
X = F, R1 = R3 = OMe, R2 = H (1a); X = F, R1 = Cl, R2 = R3 = H (1b); X = H, R1 = R3 = OMe,
R2 = H (1d); X = H, R1 = H, R2 = R3 = OMe (1e); X = H, R1 = Cl, R2 = R3 = H (1f); X = H,
R1 = R2 = OMe, R3 = H (1g); X = Cl, R1 = H, R2 = R3 = OMe (1h); X = Cl, R1 = R3 = OMe,
R2 = H (1i); Y = Br, Cl.
Scheme 2
Table 2 Yields of the precursor amines (1a–1h)
Benzyl halides
Phenoxy anilines
Target amine
Yield (%)
M.p. (8C)
2-(Bromomethyl)-1,4-dimethoxybenzene
1-(Bromomethyl)-2-chlorobenzene
2-(Bromomethyl)-1,4-dimethoxybenzene
1-(Chloromethyl)-3,5-dimethoxybenzene
1-(Bromomethyl)-2-chlorobenzene
1-(Bromomethyl)-2,3-dimethoxybenzene
1-(Chloromethyl)-3,5-dimethoxybenzene
2-(Bromomethyl)-1,4-dimethoxybenzene
5-Fluoro-2-phenoxyaniline
5-Fluoro-2-phenoxyaniline
2-Phenoxyaniline
2-Phenoxyaniline
2-Phenoxyaniline
2-Phenoxyaniline
5-Chloro-2-phenoxyaniline
5-Chloro-2-phenoxyaniline
1a
1b
1d
1e
1f
1g
1h
1i
71
75
70
45
93
65
40
73
71
Brown oil
55
59
Brown oil
78
76
55
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

¨
˚
1196 O. RAHMAN AND B. LANGSTROM
Experimental
General method for 11C-labelling synthesis
General
tetrakis(Triphenylphosphine)palladium (3.0 mg, 2.7 mmol)
was placed in a vial (1 mL), flushed with nitrogen and
anhydrous THF (200 mL) was added. The mixture was
shaken until the solution became homogeneous, and
methyl iodide (6 mL, 13.6 mg, 96.4 mmol) was added. The
mixture was heated for 5 min at 608C and the solvent
was removed by flushing with nitrogen. The residue
was dissolved in fresh anhydrous THF (250 mL). Amine
1 (14.1 mmol) was taken in another vial (1 mL), flushed
with nitrogen and dissolved in anhydrous THF (200 mL).
The solution was treated with BuLi (10 mL of 1.6 M
solution, 16.0 mmol), heated for 5 min at 608C (no
heating was needed for compound *2a) and when the
heating was finished the solvent was removed by
flushing with nitrogen. The residue was dissolved in
fresh anhydrous THF (250 mL). The two reagent solu-
tions were mixed together, filtered and loaded into the
injection loop of the equipment. From the loop, the
mixture was transferred with pressure (35 MPa) into
the micro-autoclave (200 mL), which had been pre-
charged with [11C]carbon monoxide in helium. The
micro-autoclave was immersed in an oil bath at 1508C
for 5 min. The crude product was transferred to a vial
(1 mL), THF was removed by flushing with nitrogen and
acetonitrile (1 mL) was added. The resulting solution
was injected on the semi-preparative HPLC for pur-
ification. Solvent: A1(40)–B(60) linear gradient to 0:90
within 5 min and isocratic for another 10 min, flow
5 mL/min.
All chemicals and reagents were purchased from
Aldrich or Lancaster. Freshly distilled THF (distilled
from sodium/benzophenone under nitrogen) was used
in the labelling reactions.
[
11C]Carbon dioxide was produced by the Scanditro-
nix MC-17 cyclotron at Uppsala Imanet AB using the
14N(p,a)11C reaction with 17-MeV protons in a gas
target containing nitrogen (AGA, Nitrogen 6.0) and
0.05% oxygen (AGA, Oxygen 4.8). [11C]Carbon mon-
oxide was produced by the reduction of [11C]carbon
dioxide in a zinc furnace at 4008C using a remote-
controlled work station.32
Liquid
chromatographic
(LC)
analysis
was
performed with a Beckman 126 gradient pump and a
Beckman 166 variable-wavelength UV detector in
series with
a
Bioscan bþ-flow detector. The
following mobile phases were used: 0.05 M ammonium
formate, pH 3.5 (A1); acetonitrile/H2O: 50/7 (B)
and 0.01 M formic acid in H2O (A2). For analytical
LC, a Jones Chromatography Genesis C18, 4-mm,
250 ꢂ 4.6 mm (i.d.) column was used with a flow of
1.5 mL/min. For semi-preparative LC, a Jones Chro-
matography Genesis C18, 4-mm, 250 ꢂ 10 mm (i.d.),
column was used with a flow of 5 mL/min. Synthia,33
an automated synthesis system, was used for LC
injection and fraction collection. Data collection
and LC control were performed using a Beckman
System Gold chromatography software package. Radio-
activity of products was measured in an ion chamber,
Veenstra Instrumenten bv, VDC-202. For coarse esti-
Synthesis of precursor amines 1a–1h
mations of radioactivity during the production,
a
General procedure. A suspension of activated, pow-
˚
˚
¨
portable dose-rate meter Langenas Eltekniska AB,
dered, 4-A Ms (5.00 g) and cesium hydroxide mono-
was used.
hydrate (3.12 g, 18.93 mmol) in anhydrous DMF
(100 mL) was stirred vigorously for 10 min at ambient
temperature. A solution of amine 3 (16.25 mmol) in
anhydrous DMF (10 mL) was added slowly and the
mixture was stirred for an additional 30 min at the
same temperature. Finally, a solution of benzyl halide 4
(16.25 mmol) in dry DMF (10 mL) was added to the
white suspension, and the reaction was allowed to
proceed at 708C for 4 h. The reaction mixture was
filtered to remove the undissolved materials and the
precipitate was washed with ethyl acetate (50 mL). The
filtrate was concentrated under reduced pressure and
the residue was taken up in 1 N NaOH (100 mL) and
extracted with ethyl acetate (4 ꢂ 100 mL). The com-
bined organic layers were washed with brine
(2 ꢂ 100 mL), dried over anhydrous magnesium sulfate,
filtered and the solvent was removed under reduced
pressure to give the crude product. All of the products
Non-radioactive compounds were characterized by
1H and 13C NMR spectroscopies and by gas chromato-
graphy–mass spectrometry (GC–MS). NMR spectra
were recorded on a Varian Unity-400 NMR spectro-
meter. Chloroform-d was used as the internal
standard. GC–MS was performed with a Finnigan
GCQ mass spectrometer coupled to a Finnigan Q-GC.
LC–MS was used for the final characterization
of labelled compounds and for determining the
concentration of non-radioactive products present in
the labelled products. Waters Quattra Premier micro-
mass coupled with Waters Alians LC instrument was
used for LC–MS analysis. The ionization mode used
was electrospray positive ionization (ESIþ). Mobile
phases used were B and A2. Melting points were
determined by Bibby Sterilin’s melting point apparatus
Stuart SMP3.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

SYNTHESIS OF N-(2,5-DIMETHOXYBENZYL)-N-(5-FLUORO-2-PHENOXYPHENYL) 1197
were purified by flash column chromatography (twice,
dC (100 MHz, CDCl3): 157.6, 143.1, 140.0, 136.6,
133.2, 129.8, 129.5, 128.6, 128.3, 126.9, 125.0,
122.8, 119.4, 117.4, 117.2, 111.8, 45.3.
GC–MS (EI): m=z ¼ 309:2 (Mꢀþ, 100.0%), 274.3
(10.3%), 201.1 (79.6%), 184.2 (47.8%), 166.3 (22.5%),
156.2 (14.8%), 129.2 (21.7%).
first using pentane/dichloromethane/diethyl ether
(8:1:1 v/v), then pentane/diethyl ether (8:2 v/v), as
the eluents).
N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphe-
nyl)amine 1a. dH (400 MHz, CDCl3): 7.32–7.36 (2H, m),
7.10–7.12 (1H, m), 6.98–7.01 (2H, m), 6.84–6.88 (2H,
m), 6.80–6.81 (2H, m), 6.51–6.55 (1H, m), 6.36–6.38
(1H, m), 4.91 (1H, bs), 3.36 (2H, s), 3.75 (3H, s), 3.76
(3H, s).
N-(2,3-Dimethoxybenzyl)-N-(2-phenoxyphenyl)amine
1g. dH (400 MHz, CDCl3): 7.28–7.31 (2H, m), 6.97–7.05
(5H, m), 6.84–6.90 (3H, m), 6.77–6.79 (1H, m), 6.64 (1,
m), 4.41 (2H, s), 3.86 (4H, bs), 3.83 (3H, s).
dC (100 MHz, CDCl3): 161.8, 159.5, 158.0, 153.5,
151.4, 141.9, 138.4, 129,7, 127.6, 122.5, 120.8,
116.5, 114.8, 112.3, 111.1, 102.4, 102.2, 99.4, 99.1,
55.6, 55.6, 42.8.
GC–MS (EI): m=z ¼ 353:1 (Mꢀþ, 86.6%), 322.2 (7.9%),
227.1 (14.6%), 214.2 (8.2%), 151.1 (100.0%), 121.2
(19.7%), 91.1 (23.2%), 77.1 (11.5%).
dC (100 MHz, CDCl3): 157.7, 152.7, 147.1, 143.1,
133.0, 129.7, 127.1, 125.0, 124.1, 122.7, 120.6,
119.3, 117.5, 116.9, 111.9, 111.6, 60.8, 55.8, 42.7.
GC–MS (EI): m=z ¼ 335:2 (Mꢀþ, 100.0%), 320.3
(7.7%), 304.2 (11.3%), 227.2 (11.4%), 196.2 (17.6%),
186.2 (6.7%), 167.2 (9.5%), 151.1 (46.6%), 136.1
(60.0%), 121.2 (5.4%), 91.1 (12.6%), 77.1 (5.7%).
N-(5-Chloro-2-phenoxyphenyl)-N-(3,5-dimethoxyben-
zyl)amine 1h. dH (400 MHz, CDCl3): 6.37–7.33 (11H, m),
4.79 (1H, bs), 4.28 (2H, s), 3.75 (6H, s).
N-(2-Chlorobenzyl)-N-(5-fluoro-2-phenoxyphenyl)a-
mine 1b. dH (400 MHz, CDCl3): 7.35–7.43 (4H, m), 7.25–
7.27 (3H, m), 7.13–7.15 (1H, m), 7.03–7.05 (1H, m),
6.88–6.90 (1H, m), 6.40–6.42 (2H, m), 4.90 (1H, bs),
4.49 (3H, s), 4.48 (3H, s).
dC (100 MHz, CDCl3): 161.4, 157.4, 141.4, 141.3,
130.3, 129.9, 123.2, 120.1, 117.5, 116.7, 111.7,
105.3, 99.6, 55.5, 47.9.
dC (100 MHz, CDCl3): 161.0, 160.0, 159.1, 142.0,
138.1, 135.8, 133.2, 129.8, 129.7, 128.6, 128.5, 127.0,
122.8, 120.6, 116.9, 102.8, 102.6, 99.2, 99.0, 45.2.
GC–MS (EI): m=z ¼ 327:1 (Mꢀþ, 100.0%), 292.2
(11.3%), 214.2 (17.0%), 201.1 (90.0%), 166.3 (24.9%),
125.2 (31.7%).
GC–MS (EI): m=z ¼ 369:1 (Mꢀþ, 100.0%), 338.2
(6.7%), 276.1 (12.8%), 241.2 (22.4%), 227.2 (86.8%),
212.2 (19.8%), 151.2 (72.8%), 91.1 (16.8%), 77 (9.2%).
N-(5-Chloro-2-phenoxyphenyl)-N-(2,5-dimethoxyben-
zyl)amine 1i. dH (400 MHz, CDCl3): 6.58–7.33 (11H, m),
4.82 (1H, bs), 4.34 (2H, s), 3.75 (3H, s), 3.74 (3H, s).
dC (100 MHz, CDCl3): 157.8, 154.0, 151.9, 142.0,
141.8, 130.5, 130.0, 128.1, 123.2, 120.5, 117.5,
116.6, 115.3, 113.0, 112.2, 111.7, 56.0, 43.2.
GC–MS (EI): m=z ¼ 369:1 (Mꢀþ, 55.9%), 338.1 (5.9%),
227.1 (17.4%), 151.1 (100.0%), 121.2 (16.1%), 91.1
(18.1%), 77.1 (9.6%).
N-(2,5-Dimethoxybenzyl)-N-(2-phenoxyphenyl)amine
1d. dH (400MHz, CDCl3): 7.33–7.37 (2H, m), 7.01–7.10
(4H, m), 6.92–6.93 (2H, m), 6.79–6.91 (3H, m), 6.60 (1H,
m), 4.80 (1H, bs), 4.42 (2H, s), 3.76 (3H, s), 3.75 (3H, s).
dC (100 MHz, CDCl3): 157.8, 153.6, 151.5, 142.9,
140.6, 129.6, 128.4, 125.1, 122.5, 119.6, 117.1,
116.9, 114.9, 112.2, 111.1, 55.7, 43.1.
GC–MS (EI): m=z ¼ 335:1 (Mꢀþ, 100.0%), 304.3
(15.0%), 227.2 (20.6%), 196.2 (10.0%), 151.1 (76.2%),
121.2 (17.3%), 91.1 (18.8%), 77.1 (10.4%).
Synthesis of 5-fluoro-2-phenoxyaniline 3
N-(3,5-Dimethoxybenzyl)-N-(2-phenoxyphenyl)amine
1e. dH (400 MHz, CDCl3): 7.34–7.38 (2H, m), 7.05–7.12
(4H, m), 6.93–6.95 (1H, m), 6.72–6.77 (2H, m), 6.55–
6.56 (2H, m), 6.42–6.43 (1H, m), 4.70 (1H, bs), 4.37
(2H, s), 3.79 (6H, s).
4-Fluoro-2-nitro-1-phenoxybenzene (1.51 g, 6.48 mmol),
FeCl3 ꢀ 6H2O (0.17 g, 0.61 mmol) and activated carbon
(0.17 g) were suspended in absolute ethanol (50 mL).
Hydrazine hydrate (0.7 mL, 0.72 g, 14.40 mmol) was
added, and the resulting mixture was refluxed for 4 h.
The cooled reaction mixture was filtered and the filtrate
was concentrated under reduced pressure. The residue
was partitioned between chloroform (100 mL) and
water (100 mL). The separated chloroform extract was
washed with water (3 ꢂ 100 mL), dried over anhydrous
magnesium sulfate and the solvent was removed under
reduced pressure to give the 1.27 g of the target
compound as white solid. Yield ¼ 96%, m.p. 458C.
The product was used in the next step without further
purification.
dC (100 MHz, CDCl3): 161.1, 157.6, 142.9, 142.0,
140.3, 129.7, 125.0, 122.7, 119.4, 117.3, 117.0,
111.8, 105.0, 99.2, 55.3, 47.9.
GC–MS (EI): m=z ¼ 335:2 (Mꢀþ, 100.0%), 320.3
(9.6%), 242.2 (9.1%), 227.2 (71.3%), 212.2 (15.7%),
196.2 (22.4%), 184.2 (12.2%), 151.2 (38.4%), 121.2
(4.7%), 91.1 (9.2%), 77.1 (5.2%).
N-(2-Chlorobenzyl)-N-(2-phenoxyphenyl)amine 1f. dH
(400 MHz, CDCl3): 7.40–7.45 (4H, m), 7.26–7.28 (2H,
m), 7.17 (1H, m), 7.09–7.13 (3H, m), 6.93 (1H, m),
6.73–6.76 (2H, m), 4.90 (1H, bs), 4.56 (2H, s).
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

¨
˚
1198 O. RAHMAN AND B. LANGSTROM
dH (400 MHz, CDCl3): 7.36–7.40 (2H, m), 7.14 (1H,
m), 7.03–7.05 (2H, m), 6.89–6.91 (1H, m), 6.54–6.57
(1H, m), 6.48 (1H, m), 3.99 (2H, bs).
(0.2 mL, 0.22 g, 2.80 mmol) was added slowly. The
resulting reaction mixture was allowed to warm to
ambient temperature and stirred at that temperature
for 1 h. The solvent was removed under reduced
pressure and the residue was partitioned between ethyl
acetate (75 mL) and water (100 mL). The separated
organic layer was washed with 10% CuSO4 (2 ꢂ 50 mL)
solution and water (2 ꢂ 50 mL) and dried over MgSO4.
The solvent was removed under reduced pressure to
give the target compound.
dC (100 MHz, CDCl3): 161.0, 158.6, 157.4, 140.1,
140.0, 138.3, 129.5, 122.4, 121.3, 121.2, 116.3,
104.4, 104.2, 102.8, 102.6.
GC–MS (EI): m=z ¼ 303:1 (Mꢀþ, 100.0%), 186.2
(22.1%), 174.2 (10.6%), 126.1 (16.3%), 98.1 (16.5%),
78.1 (4.3%).
Synthesis of 2-(bromomethyl)-1,4-dimethoxyben-
zene and 1-(bromomethyl)-2,3-dimethoxybenzene
4a and 4f
N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphe-
nyl)acetamide 2a. Yield 95%, white solid, m.p. 908C.
dH (400 MHz, CDCl3): 7.28–7.32 (2H, m), 7.10 (1H,
m), 6.67–6.93 (8H, m), 5.09–5.12 (1H, d), 4.63–4.66
(1H, d), 3.65 (3H, 3), 3.54 (3H, s), 1.96 (3H, s).
dC (100 MHz, CDCl3): 170.5, 159.0, 156.0, 153.5,
151.7, 148.0, 138.0, 129.8, 126.1, 123.9, 119.7,
119.6, 118.6, 117.2, 117.0, 116.4, 115.7, 115.5,
113.4, 111.3, 55.7, 55.6, 45.9, 22.1.
General procedure. Carbon tetrabromide (2.11 g,
6.50 mmol) was dissolved in dry dichloromethane and
cooled to 08C in an ice bath. 2,5- or 2,3-Dimethox-
ybenzyl alcohol was added. A solution of triphenylpho-
sphine (1.70 g, 6.48 mmol) in dry dichloromethane was
added. The reaction mixture was allowed to warm to
ambient temperature and stirred at that temperature
for 30 min. The solvent was removed under reduced
pressure. Diethyl ether (150 mL) was added and the
resulting mixture was filtered. The filtrate was concen-
trated under reduced pressure to give the crude
product, which was purified by flash column chroma-
tography using pentane/ether (9:2) as the eluent.
2-(Bromomethyl)-1,4-dimethoxybenzene 4a. Yield
85%, white crystals, m.p. 768C (lit.34 738C). dH
(400 MHz, CDCl3): 6.90 (1H, m), 6.82 (2H, m), 4.53
(2H, s), 3.85 (3H,s), 3.77 (3H, s).
GC–MS (EI): m=z ¼ 395:1 (Mꢀþ, 15.3%), 352.2 (6.9%),
302.0 (28.2%), 214.2 (8.9%), 151.1 (100.0%), 123.2
(10.2%), 91.1 (10.9%), 77.1 (6.3%).
N-(2,5-Dimethoxybenzyl)-N-(5-chloro-2-phenoxyphe-
nyl)acetamide 2i. Yield 96%, yellow solid, m.p. 1108C.
dH (400 MHz, CDCl3): 6.67–7.33 (11H, m), 4.67 (1H,
d), 5.07 (1H, d), 3.65 (3H, m), 3.54 (3H, m), 1.59 (2H,
bs).
dC (100 MHz, CDCl3): 170.6, 155.9, 153.8, 152.7,
152.1, 134.4, 130.6, 130.1, 129.0, 127.7, 126.4,
124.5, 119.4, 119.2, 116.9, 114.0, 111.6, 55.9, 55.8,
46.2, 22.3.
dC (100 MHz, CDCl3): 153.5, 151.7, 127.0, 116.4,
115.1, 112.3, 56.3, 55.8, 29.0.
GC–MS (EI): m=z ¼ 232:0 and 229.9 (Mꢀþ, 12.2 and
13.7%), 151.1 (100.0%), 121.1 (18.8%), 91.1 (30.1%),
77.1 (16.5%).
GC–MS (EI): m=z ¼ 411:0 (Mꢀþ, 10.1%), 368.1 (5.2%),
318.1 (24.2%), 230.1 (6.5%), 151.1 (100.0%), 123.2
(11.2%), 91.2 (12.7%), 77.1 (6.9%).
Conclusion
1-(Bromomethyl)-2,3-dimethoxybenzene
4f.
Yield
87%, colorless oil.
A novel method for the synthesis of [carbonyl-11C]-
DAA1106 and its analogues was described. The
carbonylation reaction using [11C]carbon monoxide,
palladium(0) complex, methyl iodide or iodobenzene
and several amines was employed in the synthesis. The
activation of amine using strong base such as n-
butyllithium (nBuLi) was used to improve the radio-
chemical yields. The presented approach has opened a
way to make a library of a series of 11C-labelled
analogues of the interesting PBR ligand DAA1106 with
moderate radiochemical yields and high specific radio-
activity.
dH (400 MHz, CDCl3): 7.01 (1H, m), 6.96 (1H, m), 6.88
(1H, m), 4.56 (2H, s), 3.96 (3H,s), 3.84 (3H, s).
dC (100 MHz, CDCl3): 152.6, 147.3, 131.6, 123.9,
122.3, 112.9, 60.6, 55.6, 28.1.
GC–MS (EI): m=z ¼ 231:9 and 229.9 (Mꢀþ, 16.1 and
16.4%), 151.1 (100.0%), 136.1 (88.5%), 121.1 (3.1%),
91.1 (16.5%), 77.1 (8.6%).
Synthesis of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-
phenoxyphenyl)acetamide and N-(2,5-dimethoxy-
benzyl)-N-(5-chloro-2-phenoxyphenyl)acetamide
2a and 2i
Acknowledgements
Uppsala Imanet and GE Healthcare are acknowledged
for financial support of this work.
General procedure. A solution of 1a or 1i (1.70 mmol)
and anhydrous pyridine (3.70 mmol) in dry THF (30 mL)
was cooled to 08C in an ice bath. Acetyl chloride
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr

SYNTHESIS OF N-(2,5-DIMETHOXYBENZYL)-N-(5-FLUORO-2-PHENOXYPHENYL) 1199
REFERENCES
20. Ferzaz B, Brault E, Bourliaud G, Robert J-P,
Poughon G, Claustre Y, Marguet F, Liere P,
¨
˚
¨
1. Bergstrom M, Grahne´n A, Langstrom B. Eur J Clin
Schumacher M, Nowicki J-P, Fournier J, Marabout
B, Sevrin M, George P, Soubrie P, Benavides J,
Scatton B. J Pharmacol Exp Ther 2002; 301:
1067–1078.
Pharmacol 2003; 59: 357–366.
˚
¨
¨
2. Langstrom B, Kihlberg T, Bergstrom M, Antoni G,
¨
Bjorkman M, Forngren BH, Forngren T, Hartvig P,
¨
Markides K, Yngve U, Ogren M. Acta Chem Scand
21. Veenman L, Gavish M. Pharmacol Ther 2006; 110:
503–524.
1999; 53: 651–669.
˚
¨
3. Rahman O, Kihlberg T, Langstrom B. Eur J Org
22. Watkins GL, Jewett DM, Mulholland GK, Kilbourn
MR, Toorongian SA. Appl Radiat Isot 1988; 39:
441–444.
Chem 2004; 474–478.
˚
¨
4. Rahman O, Llop J, Langstrom B. Eur J Org Chem
2004; 2674–2678.
23. Shah F, Hume SP, Pike VW, Ashworth S,
McDermott J. Nucl Med Biol 1994; 21: 573–581.
24. Zhang M-R, Kida T, Noguchi J, Furutsuka K,
Maeda J, Suhara T, Suzuki K, Nucl Med Biol
2003; 30: 513–519.
˚
¨
5. Karimi F, Barletta J, Langstrom B. Eur J Org Chem
2005; 2374–2378.
˚
¨
6. Kihlberg T, Langstrom B. J Org Chem 1999; 64:
9201–9205.
˚
¨
7. Rahman O, Kihlberg T, Langstrom B. J Org Chem
˚
¨
25. Rahman O, Kihlberg T, Langstrom B. J Chem Soc,
2003; 68: 3558–3562.
Perkin Trans 1 2002; 2699–2703.
˚
¨
8. Karimi F, Langstrom B. Org Biomol Chem 2003; 1:
˚
¨
26. Karimi F, Langstrom B. Eur J Org Chem 2003;
541–546.
2132–2137.
˚
¨
9. Karimi F, Kihlberg T, Langstrom B. J Chem Soc,
27. Salvatore RN, Nagle AS, Jung KW. J Org Chem
2002; 67: 674–683.
Perkin Trans 1 2001; 1528–1531.
˚
¨
10. Karimi F, Langstrom B. J Chem Soc, Perkin Trans 1
28. Okubo T, Yoshikawa R, Chaki S, Okuyama S,
Nakazato A. Bioorg Med Chem 2004; 12:
423–438.
2002; 2111–2115.
˚
¨
11. Itsenko O, Kihlberg T, Langstrom B. J Org Chem
2004; 69: 4356–4360.
29. Protiva M, Jilek J, Cervena I, Pomykacek J, Bartl V,
Dlabak A, Valchar M, Metysova J, Holubak J,
Svatek E. Collect Czech Chem Commun 1986; 51:
2598–2616.
˚
¨
12. Itsenko O, Langstrom B. J Org Chem 2005; 70:
2244–2249.
˚
¨
13. Itsenko O, Kihlberg T, Langstrom B. Eur J Org
Chem 2005; 3830–3834.
30. Fumiko Y, Tomoko N, Shuichi H, Yumiko S,
Takashi H, Masayoshi A, Hisahiro H. Helv Chim
Acta 2001; 84: 2051–2063.
14. Doi H, Barletta J, Suzuki M, Noyori R, Watanabe Y,
˚
¨
Langstrom B. Org Biomol Chem 2004; 2:
3063–3066.
31. White E. Org Synth, Collect Vol. V, 1973; 336–337.
˚
¨
15. Barletta J, Karimi F, Langstrom B. J Label Compd
˚
¨
32. Kihlberg T, Langstrom B. Method and apparatus
for production and use of [11C]carbon monoxide in
labelling synthesis. PCT International Application
No. PCT/SE02/01222.
Radiopharm 2006; 49: 429–436.
˚
¨
16. Rahman O, Kihlberg T, Langstrom B. Org Biomol
Chem 2004; 2: 1612–1616.
17. Okuyama S, Chaki S, Yoshikawa R, Ogawa S-I,
Suzuki Y, Okubo T, Nakazato A, Nagamine M,
Tomisawa K. Life Sci 1999; 64: 1455–1464.
18. Farges RC. Curr Med Chem – Anti-Inflamatory and
Anti-Allergy Agents 2003; 2: 409–416.
33. Bjurling P, Reineck R, Westerberg G, Gee AD,
˚
¨
Sutcliffe J, Langstrom B. Proceedings of the VIth
Workshop on Targetry and Target Chemistry;
TRIUMF, Vancouver, Canada, 1995; 282.
34. Brehm I, Hinneschiedt S, Meier H. Eur J Org Chem
2002; 67: 3162–3170.
19. Kruegel KE, Papadopoulos V. Annu Rev Pharmacol
Toxicol 1992; 32: 211–237.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1192–1199
DOI: 10.1002.jlcr