Utility of azetidinium methanesulfonates for radiosynthesis of 3-[ 18F]fluoropropyl amines

Article abstract of DOI:10.1002/jlcr.884

3-Methanesulfonyloxypropyl tertiary amines were observed to cyclize to form azetidinium methanesulfonate moieties. Heat-induced cyclization of 3-methanesulfonyloxypropyl amines was utilized for preparation of azetidinium methanesulfonates. The azetidinium methanesulfonates were found to incorporate radioactive [¹⁸F]fluoride (decay-corrected yields > 60%) efficiently, resulting in an efficient synthesis of 3-[¹⁸F] fluoropropyl tertiary amines. Copyright

Full text of DOI:10.1002/jlcr.884

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 953–969.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.884
Research Article
Utility of azetidinium methanesulfonates for
radiosynthesis of 3-[18F]fluoropropyl amines
Dale O. Kiesewetter* and William C. Eckelman
Positron Emission Tomography, Clinical Center, National Institutes of Health,
Bethesda, MD 20892, USA
Summary
3-Methanesulfonyloxypropyl tertiary amines were observed to cyclize to form
azetidinium methanesulfonate moieties. Heat-induced cyclization of 3-methanesulfo-
nyloxypropyl amines was utilized for preparation of azetidinium methanesulfonates.
The azetidinium methanesulfonates were found to incorporate radioactive [18F]fluor-
ide (decay-corrected yields >60%) efficiently, resulting in an efficient synthesis of 3-
[18F]fluoropropyl tertiary amines. Copyright # 2004 John Wiley & Sons, Ltd.
Key Words: fluorine-18; aliphatic fluorination; sigma receptor; radiopharmaceutical
Introduction
Although there are many strategies for preparing fluorine-containing
compounds, the introduction of [18F]fluoride (t1/2 = 109.8 min) requires
methods that incorporate fluorine very late in the synthetic scheme. The most
common aliphatic radiofluorinations are effected by treating a highly reactive
sulfonate ester precursor with [18F]fluoride in the presence of K2CO3 and
Kryptofix [2.2.2].1,2 During the course of our efforts to prepare a
methanesulfonate precursor of a hydroxypropyl amine, we observed cycliza-
tion to an azetidinium structure. We have studied the reactivity of this
azetidinium moiety toward [18F]fluoride. We also report a comparison of
radiochemical yields between the azetidinium methanesulfonate and its
analogous methanesulfonate ester.
Results and discussion
We set out to prepare F-18 labeled 4-{[1-(3-fluoropropyl)-4-piperidinyl]-
methoxy}benzonitrile ð9Þ, a compound with reportedly high selectivity for
*Correspondence to: D. O. Kiesewetter, 10/1C401, 10 Center Drive MSC 1180, National Institutes of
Health, Bethesda, MD 20892, USA. E-mail: dk7k@nih.gov
Copyright # 2004 John Wiley & Sons, Ltd.
Received 30 April 2004
Revised 4 June 2004
Accepted 16 July 2004

954
D. O. KIESEWETTER AND W. C. ECKELMAN
CN
CN
CN
O
CN
O
O
O
O
S
heat
-O
Bromopropanol
CH3SO2Cl
O
N
N+
N
N
H
(1)
O
S
OH
(2)
(4)
O
O
(3)
Scheme 1. Synthesis of azetidinium salts
sigma-1 receptors.3 The synthetic sequence for the radiolabeling employs an
alkyl methanesulfonate precursor (3, Scheme 1). The secondary amine ð1Þ was
first alkylated with bromopropanol; the resultant hydroxypropyl amine ð2Þ
was subsequently reacted with methanesulfonyl chloride to form the
methanesulfonate ester ð3Þ. Following chromatography on silica gel, an
1
impurity that later proved to be the azetidinium salt ð4Þ was observed by H-
NMR. In CHCl3 or CH3CN solution, 3 slowly converted into 4. No attempt
was made to measure the conversion rate. Once the conversion to azetidinium
4 was complete, the 1H-NMR spectrum compared favorably with that
previously reported in the literature3 for the alkylmethanesulfonate ð3Þ
(Table 1).
For the purpose of elucidating the structure, a comparative 13C-NMR
spectrum of 3 was desirable. However, the instability of 3 in solution prevented
the acquisition of the required spectrum. The conversion of 3 into 4 could be
prevented if 3 existed as a methanesulfonate salt. This salt was prepared by
reaction of alcohol 2 with methanesulfonic anhydride in the presence of
K2CO3 in a manner inspired by the method of Erhardt and Owens.4 Although
this alkyl methanesulfonate, methanesulfonate salt could not be induced to
crystallize, HPLC analysis suggested 96% purity. Because this compound also
has a positive charge on the tertiary nitrogen, its NMR spectra provided
important comparative information.
The use of conventional 1D and 2D (COSY and HETCOR) NMR
techniques provided sufficient evidence for elucidating the structure of 4 as an
azetidinium methanesulfonate. The 1D 1H-NMR and 13C-NMR peak
assignments for 4 are shown in Figures 1 and 2. An upfield CH2 signal at
%
about 14 ppm in the 13C-NMR spectrum compares favorably with that
reported in the literature for the 3-carbon of an azetidium salt.4 This
characteristic 13C resonance was observed for all the azetidinium
Copyright # 2004 John Wiley & Sons, Ltd.
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AZETIDINIUM METHANESULFONATES
955
Table 1. 1H-NMR spectra of products from the reaction of alcohol ð2Þ with
methanesulfonyl chloride
Literature
J
(4)
J
(3)b
J
(2)
J
base
(ppm)
(ppm)(3)a
(Hz) (ppm)
(Hz)
(Hz) (ppm)
(Hz)
1.65–1.8 m, 2H
2.12
1.6–1.8
2.07
m, 2H
d, 2H
1.3–1.51 m, 2H
1.7–2.1 m, 7H
1.2–1.5 m, 2H
1.7–2.09 m, 7H
d, 2H 12
14.2
2.28–2.40 m, 1H
2.75–2.88 m, 5H
2.2–2.35 m, 1H
2.77 s, 3H
2.64–2.84 m, 2H
2.46
2.94
3.01
t, 2H 6.8
d, 2H 11.2
s, 3H
2.62
3.09
t, 2H 5.9
d, 2H 11.2
3.60–3.75 m, 2H
3.62
3.92
dt, 2H 12.7, 2.9
3.93
4.05
4.39
4.5
d, 2H 6.1
d, 2H
brd, 2H
t, 2H
5.9
12.2
8.3
8.3
8.8
8.8
3.83
4.31
d, 2H 5.8 3.7–3.85 m, 4H
t, 2H 6.5
d, 2H 10
t, 2H 5.5
t, 2H 5.5
4.04
4.40*
4.51*
6.92
t, 2H
d, 2H
d, 2H
6.95
7.59
d, 2H
d, 2H
9
9
6.92
7.57
d, 2H 8.8
d, 2H 8.8
6.92
7.57
d, 2H 8.8
d, 2H 9.3
7.58
The first column is the reported literature spectrum for alkyl methanesulfonate. Compound 3 is the alkyl
methanesulfonate prior to cyclization and compound 4 is the azetidinium methanesulfonate. Literature
values obtained at 400 MHz; experimental data from this study obtained at 200 MHz.
* In more concentrated solution these signals become AB quartet (4.43 ppm).
a
1H-NMR 400 MHz reported for structure 33.
b The spectrum obtained immediately after dissolution in CDCl3.
4.4, 4.5
3.6
H
H
1.7, 2.1
4.1
H
H
H
2.7
6.9
H
2.2
H
N+
H
7.6
H
3.9
H H
H
3.6
H
H
H
4.1
H
H
H
4.4, 4.5
H
NC
O
1.7, 2.1
O
2.7
H
H
H
H
6.9
-O
S
H
7.6
(7)
O
1
Figure 1. H-NMR signal assignments of 4
methanesulfonates prepared for this study. In contrast, the methanesulfonate
1
salt of 3 showed no 13C resonance above 24 ppm. In the H-NMR, the
methanesulfonate salt of 3 contains two singlets, one for the covalently bound
methanesulfonate (3.10 ppm) and one for the ionic methanesulfonate
(2.78 ppm), while 4 shows only the ionic methanesulfonate. 4 showed an ion
of m=z ¼ 257, consistent with the cationic azetidinium moiety, upon analysis
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 953–969

956
D. O. KIESEWETTER AND W. C. ECKELMAN
64.6
60.2
59.3
N+
13.9
23.8
70.7
134.0
115.3
161.8
119.1
NC
32.4
O
104.1
O
S
39.7
(7)
-O
O
Figure 2. 13C-NMR signal assignments of 4
with ESI-MS and FAB-MS and was soluble in water. HPLC-ESI-MS of 3
showed an M+H signal at m=z 353, indicative of the covalently bound
methanesulfonate. All of this evidence supported our assignment of an
azetidinium structure for 4.
Despite the increase in strain energy, cyclization of tertiary N-3-
methanesulfonyloxypropyl moiety into an azetidinium is quite facile. Even
with the strain energy of the four-membered ring, examples of such cyclization
reactions are known to occur at room temperature to form azetidinium
salts,4,5 or azetidines.6ꢀ8 Azetidinium ring opening with nucleophiles such as
alkoxides, amines, phenoxides, cyanide, and chloride is reported to be facile.6
In addition, one literature reference demonstrated the ability of an azetidinium
methanesulfonate to serve as substrate for the incorporation of fluoride.9
We prepared several other azetidinium methanesulfonates by heat-induced
cyclization of purified methanesulfonates (Figure 3). Studies of [18F]fluoride
incorporation were undertaken to evaluate the utility of these azetidinium
methanesulfonates as substrates. The authentic fluoropropyl products were
obtained via an independent route, by treating the corresponding secondary
amine with bromofluoropropane. [18F]Fluoride reactions were conducted on
the various substrates under identical conditions (Scheme 2). Aqueous
[18F]fluoride was placed into a test tube along with Kryptofix [2.2.2] and
K2CO3. The water was removed by azeotropic drying using three portions of
CH3CN. Then, the substrates in CH3CN were added and the resulting solution
heated. HPLC buffer was added and the solution injected onto a
semipreparative C-18 HPLC column. The product peak was collected and
the radiochemical yield calculated. No attempt was made to achieve chemical
purity, but the collected product was analyzed for radiochemical purity and
identity (retention time and authentic product co-injection) on an analytical
HPLC system. The radiochemical yields, corrected for decay, under these
Copyright # 2004 John Wiley & Sons, Ltd.
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AZETIDINIUM METHANESULFONATES
957
CN
O
O
O-
O
N+
S
-O
O
S
O
N+
O
O
-O S
O
(6)
(5)
N+
F
(4)
O
O
S
O
O
S
-O
N
O
O-
N+
N
N+
(8)
(7)
Figure 3. Azetidinium methanesulfonates prepared for this study
O
-O S
K222
N
N+
K2CO3, 18F-
O
18F
6
11
R
O
-O S
R
X
X
K222
N+
N
K2CO3, 18F-
O
18F
4 X = C, R = CH2O(p-CNphenyl)
5 X = C, R = Ophenyl
7 X = N, R = 2-OCH3phenyl
8 X = N, R = 4-fluorophenyl
9
X = C, R = CH2O(p-CNphenyl)
10 X = C, R = Ophenyl
12 X = N, R = 2-OCH3phenyl
13 X = N, R = 4-fluorophenyl
Scheme 2. Radiosynthesis
conditions are reported in Table 2. All the substrates provided similar
radiochemical yields.
Three different lots of the azetidinium methanesulfonate 4 were prepared for
this study; two were prepared as described from isolated alkyl methanesulfo-
nate by cyclization in CHCl3. These two lots provided similar radiochemical
yields at 1058C and were used for the comparison reactions described in this
manuscript. The third lot was obtained by a different route. Following
Copyright # 2004 John Wiley & Sons, Ltd.
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958
D. O. KIESEWETTER AND W. C. ECKELMAN
Table 2. Radiochemical yield corrected for decay for various azetidinium methanesulfo-
nates
Substrate
NCA yield (%)
CA yield %
(5)
(6)
(7)
(8)
(4) lot 1
(4) lot 2
(4) lot 3
(3)
63 ꢁ 5a
60 ꢁ 2b
63 ꢁ 7a
66 ꢁ 5a
70 ꢁ 5b
72c
76 ꢁ 3a
86 ꢁ 3a
80 ꢁ 9a
70 ꢁ 5b
83 ꢁ 4a
NA
27 ꢁ 6a
72 ꢁ 3b
NA
NA
(NCA = no-carrier-added reaction; CA = 0.1 equivalent KF added to reaction; NA = not attempted). All
reactions run at 1058C.
a n=3.
b n=4.
c n=2 (individual values: 70, 73).
1
chromatography to isolate 3, the H-NMR showed the presence of a mixture
of 3 and 4. The mixture, in chloroform was extracted with aqueous sodium
carbonate. The aqueous layer was evaporated and the resulting solid extracted
1
with CH2Cl2. This organic soluble material gave the same H-NMR and
HPLC data as the previous two lots, but the radiochemical yield at 1058C was
significantly lower (Table 2). The melting point of the third lot obtained from
the aqueous extraction had a melting range about 108C higher than the other
two lots. We have no definitive explanation for the lower yields of the
aqueously extracted azetidinium methanesulfonate other than the possibility
that the counterion may contain some carbonate or bicarbonate.
There is one major difficulty in drawing a conclusion from these results
concerning the reactivity of the azetidinium methanesulfonates. How can we
be sure that the reaction occurred between [18F]fluoride and the azetidinium
ion? If a very small amount of the alkyl methanesulfonate was a contaminant
and this contaminant reacted very rapidly with fluoride, a high yield could be
observed even if the azetidinium salt did not react at all. The presence of minor
amounts (51%) of alkyl methanesulfonate were observed with two of the
1
substrates and could not be ruled out based on our H-NMR and HPLC
1
analyses in the others. H-NMR is not extremely sensitive to small impurities
1
and the dissolution of the sample for H-NMR or HPLC can result in
conversion of alkyl methanesulfonate into azetidinium methanesulfonate. In
order to address this issue, we studied the reaction of azetidinium salt with
addition of carrier-added [18F]fluoride. If the reaction was occurring between
fluoride and minute amounts of alkyl methanesulfonate but not with a
preformed azetidinium salt, addition of carrier fluoride should result in
lowered radiochemical yield. The various azetidinium salts (4ꢀ8) were treated
with Kryptofix [2.2.2], K2CO3, and 0.1 equivalents of KF. These carrier-added
Copyright # 2004 John Wiley & Sons, Ltd.
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AZETIDINIUM METHANESULFONATES
959
reactions resulted in the same radiochemical yield (corrected for decay) as was
observed in the no-carrier-added experiments (Table 2) for all substrates.
Therefore, the presence of minor amounts of alkyl methanesulfonate cannot
be responsible for the incorporation of [18F]fluoride.
In order to evaluate the utility of azetidinium methanesulfonates for
incorporation of non-radioactive fluoride, azetidinium 8 was treated with
[18F]fluoride, Kryptofix [2.2.2], and KF (0.88 equivalents) ðn ¼ 1Þ. Product
ð13Þ was isolated from the HPLC eluate and its identity confirmed by GC-MS
1
and H-NMR. A previous publication reported a 16% yield of fluorination
product from the reaction of Et3N-2HF with an azetidinium methanesulfonate
and concluded, ‘these ions seem quite unreactive towards fluorinating agents’.9
Contrarily, the reaction of 4 with carrier-added potassium [18F]fluoride (0.8
equivalents) and Kryptofix [2.2.2] resulted in a radiochemical yield of about
65% (decay corrected). Therefore, these azetidinium substrates may also be
useful for incorporation of non-radioactive fluoride.
Since we had determined that [18F]fluoride does react directly with the
azetidinium methanesulfonate, we compared the relative reactivity of the
azetidinium salt and alkyl methanesulfonate. Utilizing 4, the azetidinium
methanesulfonate, and 3, the corresponding alkyl methanesulfonate, a
comparison of the radiochemical yields as a function of reaction temperature
was conducted (Table 3). In order to minimize the conversion of 3 into 4 prior
to the reaction, 3 was dissolved in CH3CN immediately prior to addition to
the dried [18F]fluoride. Reducing the reaction temperature from 105 to 798C
did not significantly reduce the radiochemical yield of the no-carrier-added
reactions. Surprisingly, the radiochemical yield of 9 obtained from the alkyl
methanesulfonate was lower at 608C and much lower at 408C compared with
the yield from the azetidinium methanesulfonate. This suggests that the
azetidinium salt is actually more reactive toward fluoride and therefore, may
have applications with comparatively temperature-sensitive substrates.
At 40 and 608C, HPLC of the reaction mixture from substrate 3 indicated
that a significant amount of the alkyl methanesulfonate, 3, survived the
Table 3. Radiochemical yield corrected for decay (no-carrier-added) as a function of
temperature to compare azetidinium methanesulfonate with alkyl methanesulfonate
Temperature
(4) lot 1 azetidinium
(3) alkyl mesylate
105
79
60
41
70 ꢁ 5
72 ꢁ 3
69 (n = 2)a
56 ꢁ 12
26 ꢁ 4
65 (n = 2)b
32 (n = 2)c
1.4 ꢁ 2.0
N=3 unless otherwise stated.
a Individual numbers 72, 66.
b Individual numbers 66, 64.
c Individual numbers 33, 30.
Copyright # 2004 John Wiley & Sons, Ltd.
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960
D. O. KIESEWETTER AND W. C. ECKELMAN
reaction. This observation is consistent with the labeling studies of
Collier et al.3 in which hydroxide was added to the reaction at the end
to destroy remaining substrate 3. With all reactions utilizing 4 as substrate,
the major mass component following the reaction with [18F]fluoride was
unreacted 4.
Experimental
General
4-Hydroxybenzonitrile and 4-hydroxymethyl piperidine were purchased from
Lancaster Synthesis (Pelham, NH). Kryptofix [2.2.2] was obtained from EM
Reagents. All other reagents were purchased from Aldrich Chemical Company
(Milwaukee, WI) and used as received. Solvents were obtained from
commercial sources and used as received with the exception of tetrahydrofur-
1
an, which was distilled from sodium prior to use. H-NMR and 13C-NMR
were obtained on a Varian Gemini 2000 spectrometer at 200 and 50 MHz,
respectively. The chemical shifts are reported downfield from tetramethylsilane
(TMS). Some C-13 assignments are based on calculations using ChemDraw’s
(Ultra 8.0, CambridgeSoft, Cambridge, MA) spectrum prediction module.
HPLC-MS was obtained on a ThermoFinnigan LCQ spectrometer coupled to
a HP1100 HPLC system using electrospray as the ionization method with
HPLC employing a Phenomenex Luna C-18 (4.6 mm ꢂ 150 mm) and isocratic
elution (35% CH3CN: 65% NH4OAc) unless otherwise noted. Analytical
HPLC employed a Phenomenex C-18 column (4.6 ꢂ 150 mm) eluted with
CH3CN and NH4OAc (50 mM) at 1 ml/min. Percent purity from HPLC was
determined by integrated peak area but ignoring any peak eluting at the void
time. The calculated void volume for this column is 1.75 ml. GC-MS employed
a ThermoFinnigan TraceDSQ instrument. Gas chromatography utilized a
Restek RTX5-MS column with oven temperature programming (508C for
2 min, programmed at 308C/min to 2708C). Microanalyses were conducted by
Galbraith Laboratories, Inc. (Knoxville, TN).
1-(tert-Butyloxycarbonyl)-4-(4-cyanophenoxymethyl)piperidine
1-(tert-Butyloxycarbonyl)-4-hydroxymethyl piperidine10 (1 g, 4.65 mmol),
4-hydroxybenzonitrile (554 mg, 4.65 mmol), and triphenylphosphine (1.21 g,
4.65 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicar-
boxylate (DIAD) (1.03 g, 5.11 mmol) was added. The solution was stirred at
room temperature for 3 days. The tetrahydrofuran was evaporated, the residue
taken up in ether (50 mL) and washed with 1 M NaOH, water, and brine. The
ether layer was dried and evaporated. The residue was subjected to flash
chromatography on silica gel eluting with 20% ethyl acetate in hexane.
The major component was collected and recrystallized from ethyl acetate-
Copyright # 2004 John Wiley & Sons, Ltd.
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AZETIDINIUM METHANESULFONATES
961
hexane to yield the product (1.03 g, 69%). A trace of the diisopropyl
1,2-hydrazinedicarboxylate could be seen due to the isopropyl signals in the
1
1H-NMR. H-NMR d 1.2–1.4 (m, 2H), 1.47 (s, 9H), 1.82 (brd, 2H, J =
13.7 Hz), 1.9–2.0 (m, H), 2.75 (brt, 2H, J = 12.0 Hz), 3.85 (d, 2H, J =
1
6.4 Hz), 4.17 (brd, 2H, J = 13.2 Hz), 6.92 (d, 2H, J = 9.2 Hz), 7.58 (d, 2H,
J = 8.7). 13C-NMR d 28.6, 28.8, 28.9, 36.2, 43.6, 72.7, 79.7, 104.1, 115.3,
119.4, 134.1, 155.0, 162.4. GC-MS 8.88 min, m=z (relative abundance) 316
(M+, 3), 142 (70), 57 (100).
1-[(3-Hydroxypropyl)-4-(4-cyanophenoxymethyl)]piperidine (2)
The secondary amine (1) was obtained by treatment of 1-(tert-butyloxycarbo-
nyl)-4-(4-cyanophenoxymethyl)piperidine with trifluoroacetic acid as pre-
viously described10 and used without additional purification. 1 was alkylated
following the literature procedure3 with two minor modifications: time of
reaction and chromatography conditions. 1 (500 mg, 2.31 mmol) was dissolved
in 10 mL CH2Cl2 and anhydrous K2CO3 (956 mg, 6.93 mmol) and 3-
bromopropanol (81.1 mg, 52.7 ml, 0.575 mmol) were added. The resulting
mixture was stirred at room temperature for 4 days, at which time TLC
(silica, 90% CHCl3, 9% CH3OH, 1% NH4OH) indicated that only a small
proportion of 1 remained. Water (20 mL) and CH2Cl2 (20 mL) were added and
the layers mixed and separated. The aqueous layer was extracted with one
portion of CH2Cl2 (20 mL) and the combined organic layers were dried
(Na2SO4) and evaporated. The residue was subjected to flash chromatography,
eluting with CHCl3:MeOH:NH4OH (90:9:1) to give the desired product
1
(504 mg, 80%). H-NMR see Table 1. 13C-NMR d 27.3, 29.2, 35.8 (CH from
APT experiment), 53.7, 59.3, 64.9 (CH2OH), 72.8 (CH2OAr), 104.0, 115.3
(CN), 119.4, 134.1, 162.5.
4-Phenoxypiperidine
4-Hydroxypiperidine (2.95 g, 29.2 mmol) was dissolved in tetrahydrofuran
(40 mL) and 12 mL 10% NaOH was added.11 Di-t-butyl-dicarbonate (7.01 g,
32.1 mmol) was added dropwise over 30 min and the resulting mixture stirred
overnight. The mixture was then diluted with CHCl3 (70 mL) and partitioned
with 40 mL water. The aqueous layer was extracted with two portions of
CHCl3 (40 mL). The combined organic layers were washed with brine and
dried (Na2SO4). The organic solvent was evaporated and the residue subjected
to flash chromatography eluting with 15% ethanol in ethyl acetate. The
product (N-BOC-4-hydroxy piperidine) was collected and used in the next
step without additional purification. 1H-NMR d 1.46 (s, 3H), 1.3–1.5 (m, 2H),
1.7–1.9 (m, 2H), 2.9–3.1 (m, 2H), 3.8–3.9 (m, 3H); second t-butyl signal at 1.55
(1/3 mole equivalent).
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962
D. O. KIESEWETTER AND W. C. ECKELMAN
Crude N-BOC-4-hydroxypiperidine (2.00 g, 9.95 mmol), phenol (936 mg,
9.95 mmol) and triphenylphosphine (2.61 g, 9.95 mmol) were dissolved in THF
(40 mL). Diisopropyl azodicarboxylate (2.05 mL, 10.4 mmol) was added in one
portion. The resulting solution was stirred at room temperature for 3 h at
which time GC indicated complete conversion of N-BOC-4-hydroxypiperidine
into the phenolic ether. The solvent was then evaporated and the residue
purified by flash chromatography eluting with 10% ethyl acetate in hexane.
The product, N-BOC-4-phenoxypiperidine, was collected as a solid (1.37 g,
50%), mp 65–688C. 1H-NMR. d 1.47 (s, 9H), 1.6–2.0 (m, 4H), 3.2–3.4 (ddd, J
= 13, 3.7, 3.6 Hz, 2H), 3.6–3.8 (ddd, J = 13.7, 3.7, 3.6 Hz, 2H), 4.46 (sept, J =
3.5 Hz, 1H), 6.9–7.0 (m, 3H), 7.2–7.35 (m, 2H). 13C-NMR d 28.6, 30.7, 40.9,
72.3, 79.8, 116.4, 121.2, 129.8, 155.1, 157.4.
N-BOC-4-phenoxypiperidine (1.34 g, 4.83 mmol) was dissolved in CH2Cl2
(15 mL). Trifluoroacetic acid (4 mL) was added. The resulting solution was
stirred at room temperature for 4 h. The solvent was evaporated and the
residue taken up in CH2Cl2. The solution was washed with 30 ml 1N NaOH
and the aqueous layer was back extracted with CH2Cl2 (2 ꢂ 30 mL). The
combined organic layers were dried (Na2SO4) and evaporated. The crude title
product was obtained in 99% yield from the BOC-protected precursor and
was used directly in the next step to make the hydroxylpropyl analogue
without any additional purification. 1H-NMR d 1.6–1.8 (m, 2H), 1.95–2.1 (m,
2H), 2.65–2.80 (m, 2H), 3.1–3.2 (m, 2H), 4.37 (sept, J = 4.1 Hz, 1H), 6.9–7.0
(m, 3H), 7.2–7.35 (m, 2H).
3-[4-(2-Methoxyphenyl)piperazin-1-yl]propan-1-ol
The corresponding secondary amine (1.32 g, 6.86 mmol) was dissolved in
CH2Cl2 (25 mL) and treated with 3-bromopropanol (1.15 g, 8.24 mmol) and
K2CO3 (2.94 g, 20.6 mmol).12 The reaction was stirred at room temperature for
three days and refluxed for 8 h. The mixture was diluted with water and the
layers separated. The organic phase was dried with Na2SO4 and evaporated.
The residue was chromatographed on silica gel, eluting with chloroform:
methanol:ammonia (90:9:1) to obtain the amino alcohol containing 3-
bromopropanol as a minor contaminant. The desired product was obtained
by formation of the oxalate followed by conversion to the free base (952 mg,
55%).
1H-NMR d 1.76 (quin, J = 6 Hz, 2 H), 2.62–2.84 (m, 7H), 3.00–3.20 (brs,
5H), 3.75–3.90 (m, 2H), 3.85 (s, 2H), 6.8–7.1 (m, 4 H).
3-(4-Phenoxypiperidin-1-yl)propan-1-ol
This compound was prepared in 42% yield following the method for 3-(4-
(2-methoxyphenyl)piperazin-1-yl)propan-1-ol. 1H-NMR. d 1.67–2.05 (m, 6H),
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AZETIDINIUM METHANESULFONATES
963
2.25–2.35 (m, 2H), 2.63 (t, J = 5.2 Hz, 2H), 2.7–2.9 (m, 2H), 3.82 (t, J =
5.2 Hz, 2H), 4.36 (sept, J = 3 Hz, 1H), 5.44 (br s, 1H), 6.8–7.0 (m, 3H), 7.20–
7.35 (m, 2H).
3-[Methyl(2-phenylethyl)amino]-1-propanol
The corresponding secondary amine was dissolved in DMF (1.5 mL/mmol)
and treated with 1.05 equivalent of bromopropanol and 1.5 equivalents of
diisopropyl ethylamine.13 The resulting solution was heated at 808C for 3 days.
The reaction was cooled, diluted with water and extracted with three portions
of ether. The organic extracts were dried and the solvent evaporated. The
residue was subjected to flash chromatography on silica gel eluting with
chloroform:methanol: ammonia (90:10:1). The product was obtained as an oil
(63%). A small amount of DMF was present, but the sample was utilized in
1
the next step without additional purification. H-NMR d 1.70 (quin, J =
5.4 Hz, 2H), 2.33 (s, 3H), 2.60–2.68 (m, 4H), 2.68–2.81 (m, 2H), 3.78 (t, J =
4.7 Hz), 7.10–7.35 (m, 5H).
3-(4-(4-Fluorophenyl)piperazin-1-yl)propan-1-ol
This compound was prepared in 70% yield following the same method as for
3-[methyl(2-phenylethyl)amino]-1-propanol.14
1H-NMR d 1.76 (quin, J = 5.4, 2H), 2.6–2.7 (m, 6H), 3.05–3.12 (m, 4H),
3.83 (t, J = 5.2 Hz, 2H), 5.0 (br s, 1H), 6.8–7.00 (m, 4 H).
3 -(4-((4-Cyanophenoxy)methyl)piperidin-1-yl)propyl methanesulfonate, methane-
sulfonate salt (3, methanesulfonate salt)
2 (100 mg, 0.365 mmol) was dissolved in CH2Cl2 (6 mL) and treated with
methanesulfonic anhydride (127 mg, 0.730 mmol) and K2CO3 (201 mg,
1.46 mmol). The reaction was stirred at room temperature overnight, filtered
through Celite and evaporated. The resulting oil was triturated at dry ice
temperature with ether and the ether decanted. Crystallization from 2-
propanol was unsuccessful leading to an oil. The solvent was decanted, the
residue taken up in CHCl3 and CH3CN and evaporated to provide 84 mg
(50%) as an oil. HPLC (35% CH3CN) TR 6.4 min, 96% at 230 nm. HPLC
(Phenomenex Luna (2 ꢂ 150 mm, 100% 50 mM NH4OAc to 65% CH3CN,
1
35% 50 mM NH4OAc over 10 min, 1 ml/min) ESI-MS m=z 353 (M+H). H-
NMR d 1.82–2.24 (m, 5H), 2.24–2.55 (m, 2H), 2.78 (s, 3H), 2.75–3.00 (m, 2H),
3.10 (s, 3H), 3.18–3.42 (m, 2H), 3.70 (brd, J = 11 Hz, 2H), 3.92 (d, J = 5.0 Hz,
2H), 4.40 (t, J = 4.9 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.7 Hz,
2H), 10.34 (brs, 1H). Some impurity signals were observed. 13C-NMR d 24.2,
25.9, 33.8, 37.5 (CH3), 39.7 (CH3), 52.9, 54.2, 67.2, 71.2, 104.3, 115.3 (CH),
119.2, 134.1(CH), 161.8.
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D. O. KIESEWETTER AND W. C. ECKELMAN
General synthesis method for azetidinium methanesulfonates
The appropriate 3-hydroxypropylamine was dissolved in dichloromethane and
treated with 1.1 equivalent of methanesulfonyl chloride and 4 equivalents of
triethylamine. The reaction was stirred at room temperature for 30–45 min.
The solvent was evaporated and the residue subjected to flash chromatography
on silica gel. The sample was loaded in ethyl acetate and the column eluted
with 10% ethanol in ethyl acetate (unless otherwise stated). This procedure
follows the literature preparation of 3 except for a change in the eluant for the
silica gel column purification.3 Fractions containing product were collected
1
and the solvent evaporated in vacuo with a bath temperature of 258C. H-
NMR was acquired on these intermediates; spectra showed a preponderance
of alkyl methanesulfonate with varying amounts of azetidinium salts. The
product mixtures were dissolved in chloroform and heated at 658C overnight
to effect complete cyclization to the azetidinium methanesulfonate. The
solvent was evaporated and the resulting oil triturated with ethyl acetate. Two
of the five azetidinium methanesulfonates did not solidify upon trituration.
7-[(4-Cyanophenoxy)methyl]-4-azoniaspiro[3.5]nonane methanesulfonate (4)
Following the general procedure for azetidinium methanesulfonates, alkyl
methanesulfonate 3 was obtained as a solid in 72% yield (mp 72–748C, lit.3
1
67–688C). H-NMR of ð3Þ is reported in Table 1. Analytical HPLC (35%
CH3CN) showed two components 3.17 min (azetidinium 4) and 6.69 min (alkyl
methanesulfonate 3). Following cyclization, recovery of hygroscopic azetidi-
nium methanesulfonate 4 from alkyl methanesulfonate 3 was 89% (overall
yield from alcohol 65%). mp 139–1418C. 1H-NMR for 4 is reported in Table 1
and Figure 1. 13C-NMR is reported in Figure 2. HPLC-ESI-MS: m=z 257.
HPLC (20% CH3CN) 7.46 min, 99% at 250 nm.
Analysis: Calculated for C17H24N2O4S ꢃ 1/3 H2O: C, 56.96; H, 6.94; N,
7.82; S, 8.95. Found: C, 57.36; H, 6.79; N, 7.81; S, 8.56.
A second sample was obtained in a similar manner, mp 135–1388C. A third
sample of 4 was obtained from the alkyl methanesulfonate by partitioning
with aqueous Na2CO3 and evaporating the aqueous layer. The residue from
the aqueous layer was washed with CH2Cl2 and evaporated to yield an oil.
This oil was crystallized from 2-propanol, mp 150–1538C. FAB-MS
1
m=z þ 257. H-NMR for lots 2 and 3 were identical to lot 1.
7-Phenoxy-4-azoniaspiro[3.5]nonane methanesulfonate (5)
Following the general procedure for azetidinium methanesulfonates, the alkyl
methanesulfonate precursor of 5 was prepared. Chromatography of alkyl
methanesulfonate utilized 10% acetonitrile in ethyl acetate to give 87% yield.
1H-NMR of alkyl methanesulfonate showed CH3 at 3.02 ppm and
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AZETIDINIUM METHANESULFONATES
965
CH2OSO2CH3 at 4.3 ppm (t). The azetidinium methanesulfonate, resulting
from heat-induced cyclization, did not solidify upon treatment with ethyl
acetate. The resulting oil solidified after standing overnight at ꢀ208C, but
melted on warming to room temperature. The product contained 51% alkyl
1
methanesulfonate as determined by H-NMR.
1H-NMR d 2.0–2.3 (m, 4H), 2.79 (s, 3H), 2.82 (quin, J = 8.3 Hz, 2H), 3.61
(dt, J = 12, 3.4 Hz, 2H), 3.97 (t, J = 4.0, 1H), 4.03 (t, J = 4.4 Hz, 1H), 4.40,
(t, J = 8.3 Hz, 2H), 4.63 (t, J = 8.3 Hz, 2H), 6.89 (d, J = 7.8 Hz, 2H), 7.00 ( t,
J = 7.3 Hz, 1H), 7.30 (t, J = 8.3 Hz, 2H).
13C-NMR d 156.25, 130.0, 122.1, 116.2, 66.6, 63.9, 61.4, 56.3, 39.9, 25.8,
14.1.
HPLC-ESI-MS: m=z 218. HPLC (20% CH3CN): TR 6.5 min, 95% purity at
250 nm.
Analysis: Calculated for C15H23NO4S: C, 57.48; H, 7.40; N, 4.47; S, 10.23.
Found: C, 54.79, H, 7.49, N, 4.20, S, 9.94.
1-Methyl-1-(2-phenylethyl)azetidinium methanesulfonate (6)
Following the general procedure for azetidinium methanesulfonates, the alkyl
1
methanesulfonate was obtained in 85% yield. H-NMR of alkyl methane-
sulfonate showed CH3 at 2.95 ppm and CH2OSO2CH3 at 4.20 ppm. Following
cyclization, the azetidinium methanesulfonate was recovered as a hygroscopic
solid in 70% yield after trituration with EtOAc. mp 83–858C. 1H-NMR d 2.72
(s, 3H), 2.45–2.9 (m, 2H), 2.95–3.05 (m, 2H), 3.35 (s, 3H), 3.75–3.90 (m, 4H),
4.2–4.4 (m 2H), 4.4–4.65 (m, 2H), 7.2–7.4 (m, 5H). 13C-NMR d 135.3, 129.2,
129.2, 127.6, 65.1, 64.4, 49.1, 39.9, 29.7, 14.3.
HPLC-ESI-MS: m=z 176. HPLC (20% CH3CN): TR 4.1 min, 95% purity at
250 nm.
Analysis: Calculated for C13H21NO3S ꢃ 1 H2O: C, 55.69; H, 7.91; N, 5.00; S,
11.44. Found: C, 55.29; H, 7.99, N, 5.62, S, 11.06.
2
7-(2-Methoxyphenyl)-7-aza-4-azoniaspiro[3.5]nonane methanesulfonate (7)
Following the general procedure for azetidinium methanesulfonates, the alkyl
methanesulfonate was obtained in 83% yield. 1H-NMR of the alkyl
methanesulfonate showed OCH3 at 3.05 ppm and CH2OSO2CH3 at
4.33 ppm. Following cyclization, 7 was obtained as an oil and could not be
induced to solidify. 7 was observed to contain 51% alkyl methanesulfonate
1
by H-NMR.
1H-NMR d 2.76 (s, 3H), 2.84 (quin, J = 8.3 Hz, 2H), 3.2–3.3 (m, 4H), 3.83
(s, 3H), 3.8–3.9 (m, 4H), 4.54 (t, J = 8.0 Hz, 4H), 6.8–7.9 (m, 3H), 7.0–7.15 (m,
1H). 13C-NMR d 152.3, 138.6, 124.6, 121.2, 118.9, 111.6, 62.4, 59.9, 55.6, 45.5,
39.8, 14.1. HPLC-ESI-MS: m=z 233. Analytical HPLC (35% CH3CN): TR
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D. O. KIESEWETTER AND W. C. ECKELMAN
4.5 min, 97% purity at 250 nm. Analysis: Calculated for C15H24N2O5S H2O:
C, 52.00; H, 7.56; N, 8.09; O, 23.09; S, 9.26. Found: C, 52.08; H, 7.02; N, 7.91;
S, 9.36.
7-(4-Fluorophenyl)-7-aza-4-azoniaspiro[3.5]nonane methanesulfonate (8)
Following the general procedure for azetidinium methanesulfonates, the alkyl
1
methanesulfonate was obtained in 86% yield. H-NMR of alkyl methane-
sulfonate d 1.97 (pent, J = 6.8 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 2.55–2.65 (m,
4H), 3.02 (s, 3H), 3.05–3.15 (m, 4H), 4.33 (t, J = 6.3 Hz, 2H), 6.8–7.05 (m,
4H). Following cyclization, 8 was obtained as a hygroscopic solid in 86% yield
1
from the alkyl methanesulfonate. mp 143.5–1468C. H-NMR d 2.75 (s, 3H),
2.82 (quin, J = 8.3 Hz, 2H), 3.2–3.3 (m, 4H), 3.8–3.9 (m, 4H), 4.55 (t, J =
8.3 Hz, 4H), 6.8–7.1 (m, 4H). 13C-NMR d 158.2 (J = 241 Hz), 145.8 (J =
2.4 Hz), 119.1 (J = 7.8 Hz), 116.1 (J = 22.4 Hz), 62.4, 59.3, 45.7, 39.9, 14.1.
HPLC-ESI-MS: m=z 221. HPLC (20% CH3CN): TR 2.97 min, 97% purity at
250 nm.
Analysis: Calculated for C14H21FN2O3S ꢃ 1/3 H2O: C, 52.16; H, 6.77; N,
8.69; S, 9.95. Found: C, 52.55; H, 6.82; N, 8.68; S, 9.69.
General procedure for preparation of fluoropropyl analogues
Secondary amine (1 equivalent) was dissolved in a solvent (CH2Cl2, CH3CN,
or DMF). 1-Bromo-3-fluoropropane (1.02 equivalent) and base (K2CO3, 4
equivalents; or diisopropyl amine, 1.5 equivalents) were added. The reaction
was stirred at room temperature for 2 days (CH2Cl2), heated at 858C overnight
(CH3CN) or heated at 608C for 3–4 days (DMF). The reaction was partitioned
with water, evaporated and dried (Na2SO4). The product was purified by flash
chromatography on silica gel. The free base was precipitated from acetone
solution by addition of oxalic acid.
4-{[1-(3-Fluoropropyl)-4-piperidinyl]methoxy}benzonitrile (9)3
Using the general procedure, alkylation was conducted in CH2Cl2 for 2 days.
Flash chromatography employed CHCl3:MeOH:NH4OH (95:4.5:0.5). The
free base was analyzed by GC-MS (EI), TR 8.23 min, 276 (4), 230 (100).
1
The oxalate was obtained in 51% yield. H-NMR (oxalate salt in CDCl3/
DMSO-d6) d 1.8–2.4 (m, 7H), 2.65–2.9 (m, 2H), 3.1–3.25 (m, 2H), 3.68 (br d,
J = 7.8 Hz, 2H), 3.90 (d, J = 7.8 Hz, 2H), 4.53 (dt, J = 46.9, 5.4 Hz, 2H), 6.93
(d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H). HPLC (35% CH3CN) TR
5.5 min, >98% at 230 nm.
Analysis: Calculated for C16H21FN2O ꢃ C2H2O4: C, 59.01; H, 6.33; N, 7.65.
Found: C, 58.75; H, 6.49; N, 7.58.
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AZETIDINIUM METHANESULFONATES
967
1-(3-Fluoropropyl)-4-phenoxypiperidine (10)
Following the general procedure, alkylation was conducted in CH3CN at 858C
overnight. The free base was obtained in 92% yield following flash
chromatography (CHCl3:MeOH:NH4OH (95:4.5:0.5)) and characterized by
1H-NMR. The oxalate salt was obtained in 71% yield. GC-MS (EI) TR
7.6 min 237 (15), 190 (100), 144(45). HPLC (35% CH3CN) TR 7.6 min, >99%
1
at 230 nm. H-NMR (free base) d 1.7–2.1 (m, 6H), 2.2–2.4 (m, 2H), 2.48 (two
overlapping doublets, J = 7.8, 6.8, 2H), 4.35 (sept, J = 3.9 Hz, 1H), 4.50 (dt, J
= 47.4, 5.9 Hz), 6.8–7.0 (m, 3H), 7.2–7.35 (m, 2H). 13C-NMR d 157.6, 129.6,
120.9, 116.3, 82.7 (J = 164), 72.7, 54.4 (J = 5.9), 50.8, 31.0, 28.4 (J = 19.5).
Analysis: Calculated for C14H20FNO ꢃ C2H2O4: C, 58.71; H, 6.77; N, 4.28.
Found: C, 58.12; H, 6.85, N, 4.26.
N-(3-Fluoropropyl)-N-methyl-N-(2-phenylethyl)amine (11)
Using the general procedure, alkylation was conducted in DMF for 3 days.
The free base was isolated after flash chromatography (CHCl3:MeOH:N-
H4OH (95:4.5:0.5)) and analyzed by NMR. The oxalate salt was obtained in
63% overall yield. GC-MS (CI-CH4) TR 4.99 min. 196 (M+1). HPLC (35%
CH3CN) TR 4.8 min, >98% at 230 nm. 1H-NMR d (free base) 1.70–2.0 (dm, J
= 25.4, 2H), 2.30 (s, 3H), 2.53 (t, 7.0), 2.55–2.65 (m, 2H), 2.65–2.80 (m, 2H),
4.46 (dt, J = 47.3, 5.8 Hz, 2H), 7.1–7.35 (m, 5H). 13C-NMR d 140.7, 128.9,
128.5, 126.1, 82.7 (J = 163.6), 59.8, 53.4 (J = 5.3), 42.3, 34.0, 28.6 (J = 9.6).
Analysis: Calculated for C12H18FN ꢃ C2H2O4: C, 58.94; H, 7.17; N, 4.91.
Found: C, 58.85; H, 7.17; N, 4.91.
1-(3-Fluoropropyl)-4-(2-methoxyphenyl)piperazine (12)
Following the general procedure, alkylation was conducted in DMF for 3
days. The free base was isolated by flash chromatography (CHCl3:MeOH:
NH4OH (95:4.5:0.5)). The oxalate was obtained in 86% overall yield. GC-MS
(CI-CH4) TR 6.92 min, 253 (M+1), 281 (M+29). HPLC (35% CH3CN) TR
1
7.0 min, >99% at 230 nm. H-NMR (free base) d 1.8–2.1 (dm, J = 25.4 Hz,
2H), 2.55 (t, J = 7.3 Hz, 2H), 2.6–2.7 (m, 4H), 3.05–3.15 (m, 4H), 3.85 (s, 3H),
4.53 (dt, J = 47.4, 5.8 Hz, 2H), 6.8–7.1 (m, 4H). 13C-NMR d 152.5, 141.5,
123.1, 121.1, 118.4, 111.4, 82.8 (J = 164), 55.5, 54.5 (J = 5.4), 53.6, 50.8, 28.1
(J = 20). Analysis: Calculated for C14H21FN2O ꢃ C2H2O4: C, 56.13; H, 6.77;
N, 8.18. Found: C, 54.22; H, 6.67; N, 7.58.
1-(4-Fluorophenyl)-4-(3-fluoropropyl)piperazine (13)
Following the general procedure, alkylation was conducted in DMF for 4
days. After flash chromatography (CHCl3:MeOH:NH4OH (97:2.7:0.3)) 13
was obtained in 89% yield. The oxalate salt was obtained in 88% overall yield.
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968
D. O. KIESEWETTER AND W. C. ECKELMAN
GC-MS (CI-CH4) TR 6.48 min, 241(M+1), 221 ((M+1)–20). HPLC (35%
1
CH3CN) TR 13.1 min, >99% at 230 nm. H-NMR (free base) d 1.75–2.05
(dm, J = 24.9 Hz, 2H), 2.53 (t, J = 7.3, 2H), 2.5–2.7 (m, 4H), 3.0–3.2 (m, 4H),
4.55 (dt, J = 47.3, 5.9 Hz, 2H), 6.8–7.0 (m, 4H).
Analysis: Calculated for C13H18F2N2 ꢃ C2H2O4: C, 54.54; H, 6.10; N, 8.48.
Found: C, 54.63; H, 6.38; N, 8.19.
Radiofluorination of azetidinium methanesulfonates
Stock solutions of Kryptofix [2.2.2] (9 mg/100 mL), K2CO3 (0.1 M), and KF-
H2O (0.147 M) were prepared. A 13 ꢂ 100 mm test tube was charged with
100 mL (24 mmol) of Kryptofix [2.2.2] solution, 120 mL (12 mmol) K2CO3
solution, and an aliquot of [18F]fluoride (1–5 mCi). The solvents were
evaporated under a stream of argon while heating at 100–1108C. Three
portions of CH3CN (200 mL) were added and each, in turn, evaporated. A
solution of the azetidinium methanesulfonate (5.7 mmol) in 300 mL CH3CN
was added and heated for 5 min in the same heating block. The reaction
solution was then removed from heat, cooled briefly, and diluted with 500 mL
of 50 mM NH4OAc solution. (If the reaction went dry during heating, CH3CN
(200 ml) was added first.) The entire solution was injected onto a semipre-
parative HPLC column (Phenomenex Luna C-18(2) 9.4 ꢂ 250 mm) and eluted
with 30% CH3CN, 70% 50 mM NH4OAc at 5 ml/min. The eluate was
monitored with online radioactivity and UV detectors (230 nm). The two
largest radioactivity peaks, [18F]fluoride, near the solvent front, and product,
at the appropriate retention time, were collected. Radioactivity assay of the
product was corrected for decay to the start of the reaction and the decay
corrected radiochemical yield calculated. An aliquot of the product was
reinjected onto an analytical HPLC column (Phenomenex Luna C-18(2)
4.6 ꢂ 150 eluted with 35% CH3CN: 65% 50 mM NH4OAc at 1 mL/min) to
verify radiochemical purity and identity based on retention time. The retention
time for each individual fluorinated product on the analytical system can be
found with its experimental description above.
Conclusion
A variety of quaternary azetidinium methanesulfonates were prepared with a
relatively facile cyclization procedure that involved heating of the alkyl
methanesulfonate in chloroform. Azetidinium methanesulfonates could be
used as substrate for incorporation of both no-carrier-added and carrier-
added [18F]fluoride. At 40 and 608C the azetidinium methanesulfonate 4
provided a higher radiochemical yield based on [18F] fluoride than the
corresponding alkyl methansulfonate 3. Higher radiochemical yields are
obtained at the higher temperatures studied but either substrate provided
equivalent yields.
Copyright # 2004 John Wiley & Sons, Ltd.
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AZETIDINIUM METHANESULFONATES
969
Acknowledgements
The authors thank Dr. Ying Ma of the radiochemistry group for HPLC-MS
analysis and Mr. Victor Livengood of the Laboratory of Analytical
Chemistry, NIDDK for FAB-MS analysis. We thank Dr. Mark B. Sassaman
of the Positron Emission Tomography Department for a critical review of this
manuscript.
References
1. Hamacher K, Coenen HH, Stocklin G. J Nucl Med 1986; 27: 235–238.
2. Lasne MC, Perrio C, Rouden J, Barre L, Roeda D, Dolle F, Crouzel C. Contrast
Agents II: Top Curr Chem 2002; 222: 201–258.
3. Collier TL, O’Brien J, Waterhouse RN. J Label Compd Radiopharm 1996; 38:
785–794.
4. Erhardt PW, Owens AH. Synth Commun 1987; 17: 469–475.
5. Ringdahl B, Roch M, Jenden DJ. J Med Chem 1988; 31: 160–164.
6. Moore JA, Ayers RS. The Chemistry of Heterocyclic Compounds, vol. 42, Wiley:
New York, NY, 1983; 1–218.
7. Leonard NJ, Durand DA. J Org Chem 1968; 33: 1322–1333.
8. Wieland DM, Kilbourn MR, Yang DJ, Laborde E, Gildersleeve DL, VanDort
ME, Pirat JL, Ciliax BJ, Young AB. Appl Radiat Isotop 1988; 39: 1219–1225.
9. Giudicelli MB, Picq D, Anker D. Tetrahedron 1992; 48: 6033–6042.
10. Waterhouse RN, Collier TL, O’Brien JC. J Label Compd Radiopharm 1996; 38:
215–226.
11. Boswell RF, Helsley GC, Duncan RL, Funderburk WH, Johnson DN. J Med
Chem 1974; 17: 1000–1008; Knutsen LJK, Lau J, Sheardown MJ, Thomsen C.
Biorg Med Chem Lett 1993; 3(12): 2661–2666.
12. Elworthy TR, Ford APDW, Bantle GW, Morgans DJ, Ozer RS, Palmer WS,
Repke DB, Romero M, Sandoval L, Sjogren EB, Talamas FX, Vazquez A, Wu H,
Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD,
Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE. J Med Chem 1997; 40:
2674–2687.
13. Rider ES, Cook TH. J Am Chem Soc 1936; 58: 1079–1081.
14. Claudi F, Giorgioni G, Scoccia L, Ciccocioppo R, Panocka I, Massi M. Eur J
Med Chem 1997; 32: 651–659.
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